Production method of imidazole derivatives

ABSTRACT

The present invention provides an advantageous production method of an imidazole derivative, which is suitable for industrial production. Compound (VI) is produced by reacting compound (I) with a Grignard reagent or a magnesium reagent, and a lithium reagent, and then reacting the resulting compound with compound (V).

CROSS REFERENCE TO RELATED APPLICATION

The present application is a divisional application of the U.S. PatentApplication No. 14/123,381 filed Dec. 2, 2013, which was the NationalPhase Application of the International Patent Application No.PCT/JP2012/065795 filed Jun. 14, 2012, which also claimed the benefit ofpriority of the Japanese Patent No. 2011-133712 filed Jun. 15, 2011. Theentire contents of those applications are incorporated herein for allpurposes by this reference.

TECHNICAL FIELD

The present invention relates to an industrially advantageous productionmethod of an imidazole derivative.

BACKGROUND OF THE INVENTION

It is known that an imidazole derivative represented by the followingformula (Ia):

wherein n is an integer of 1 to 3, and Ar is an aromatic ring optionallyhaving substituent(s), or a salt thereof has high safety and superiorsteroid C₁₇₋₂₀ lyase inhibitory activity, and is useful for theprophylaxis or treatment of diseases for which androgen or estrogen isan aggravating factor (patent document 1).

As the production method of the above-mentioned imidazole derivative,the methods described in patent document 1 and patent document 2 areknown.

However, there is a demand for an advantageous production method of theimidazole derivative, which is suitable for industrial production.

DOCUMENT LIST Patent Document

-   Patent Document 1: WO 02/40484-   Patent Document 2: WO 03/059889

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

In the production method of patent document 2, the synthetic reaction ofthe following formula (Ib):

wherein Ar is an aromatic hydrocarbon group optionally havingsubstituent(s), and PG is an imidazole-protecting group, which is anintermediate for synthesizing the above-mentioned formula (Ia), needs tobe carried out in the presence of an organic lithium compound at anultralow temperature of −65° C.

In view of such situation, an object of the present invention is toprovide a novel production method of an imidazole derivative representedby the above-mentioned formula (1a), particularly6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-napht-hamideor a salt thereof, which is suitable for efficient and convenientindustrial production. In addition, another object of the presentinvention is to provide a production method of a compound useful as anintermediate for synthesizing6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-napht-hamideor a salt thereof, specifically the below-mentioned compound (VI) andcompound (IX), which is suitable for efficient and convenient industrialproduction.

Means of Solving the Problems

The present inventors have conducted intensive studies in an attempt tosolve the above-mentioned problems and found that the synthetic reactionof a compound represented by the above-mentioned formula (1b),particularly the below-mentioned compound (VI), can proceed under mildconditions by using an organic magnesium compound together with anorganic lithium compound, which resulted in the completion of thepresent invention.

Accordingly, the present invention is as follows; [1] A method ofproducing a compound represented by the formula:

-   wherein PG is a protecting group,-   or a salt thereof (hereinafter sometimes to be referred to as    compound (VI)), which comprises Step (1): a step of reacting a    compound represented by the formula:

-   wherein R¹ is an iodine atom or a bromine atom,-   (hereinafter sometimes to be referred to as compound (I)) with a    compound represented by the formula:

R²—MgX   (II)

-   wherein R² is a C₁₋₆ alkyl group or a C₆₋₁₂ aryl group; and X is a    chlorine atom, a bromine atom or an iodine atom, (hereinafter    sometimes to be referred to as compound (II)), or a compound    represented by the formula:

R^(22′)—Mg   (III)

-   wherein R^(2′) is a C₁₋₆ alkyl group or a C₆₋₁₂ aryl group; and R²    is as defined above,-   (hereinafter sometimes to be referred to as compound (III)), and a    compound represented by the formula:

R³—Li   (IV)

-   wherein R³ is a C₁₋₆ alkyl group or a C₆₋₁₂ aryl group, (hereinafter    sometimes to be referred to as compound (IV)), and then reacting the    resulting compound with a compound represented by the formula:

-   wherein PG is as defined above,-   or a salt thereof (hereinafter sometimes to be referred to as    compound (V)).-   [2] A method of producing    6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-napht-hamide    or a salt thereof, which comprises-   Step (1): a step of reacting a compound represented by the formula:

-   wherein R¹ is an iodine atom or a bromine atom, with a compound    represented by the formula:

R²—MgX   (II)

-   wherein R² is a C₁₋₆ alkyl group or a C₆₋₁₂ aryl group; and X is a    chlorine atom, a bromine atom or an iodine atom, or a compound    represented by the formula:

R²R^(2′)—Mg   (III)

-   wherein R^(2′) is a C₁₋₆ alkyl group or a C₆₋₁₂ aryl group; and R²    is as defined above, and a compound represented by the formula:

R³—Li   (IV)

-   wherein R³ is a C₁₋₆ alkyl group or a C₆₋₁₂ aryl group, and then    reacting the resulting compound with a compound represented by the    formula:

-   wherein PG is a protecting group,-   or a salt thereof;-   Step (2): a step of subjecting a compound represented by the    formula:

-   wherein PG is as defined above,-   or a salt thereof, (hereinafter sometimes referred to as compound    (VI)), which is obtained in Step (1), to oxidation; Step (3): a step    of reacting a compound represented by the formula:

-   wherein PG is as defined above,-   or a salt thereof (hereinafter sometimes to be referred to as    compound (VII)), which is obtained in Step (2), with a compound    represented by the formula:

BrZnCH₂CO₂—R⁴   (VIII)

-   wherein R⁴ is a C₁₋₆ alkyl group,-   (hereinafter sometimes to be referred to as compound (VIII)); Step    (4): a step of subjecting a compound represented by the formula:

-   wherein each symbol is as defined above,-   or a salt thereof (hereinafter sometimes to be referred to as    compound (IX)), which is obtained in Step (3), to reduction; and-   Step (5): a step of subjecting a compound represented by the    formula:

-   wherein PG is as defined above,-   or a salt thereof (hereinafter sometimes to be referred to as    compound (X)), which is obtained in Step (4), to cyclization and    deprotection.-   [3] A method of producing of a compound represented by the formula:

-   wherein PG is a protecting group; and R⁴ is a C₁₋₆ alkyl group,-   or a salt thereof, which comprises-   Step (3a): a step of reacting a compound represented by the formula:

-   wherein PG is as defined above,-   or a salt thereof, with a compound represented by the formula:

BrZnCH₂CO₂—R⁴   (VIII)

-   wherein R⁴ is as defined above,-   and then adding citric acid to the obtained reaction mixture.-   [4] A method of producing of    6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-napht-hamide    or a salt thereof, which comprises-   Step (3a): a step of reacting a compound represented by the formula:

-   wherein PG is a protecting group,-   or a salt thereof, with a compound represented by the formula

BrZnCH₂CO₂—R⁴   (VIII)

-   wherein R⁴ is a C₁-₆ alkyl group,-   and then adding citric acid to the obtained reaction mixture;-   Step (4): a step of subjecting a compound represented by the    formula:

-   wherein each symbol is as defined above,-   or a salt thereof, which is obtained in Step (3a), to reduction; and-   Step (5): a step of subjecting a compound represented by the    formula:

-   wherein PG is as defined above,-   or a salt thereof, which is obtained in Step (4), to cyclization and    deprotection.-   [5] The method of any of the above-mentioned [1] to [4], wherein PG    is trityl.-   [6] The method of any of the above-mentioned [1] to [4], wherein PG    is tosyl, benzenesulfonyl or N,N-dimethylaminosulfonyl.-   [7] The method of the above-mentioned [2], wherein Step (3) is Step    (3a): a step of reacting a compound represented by the formula:

-   wherein PG is a protecting group,-   or a salt thereof, with a compound represented by the formula:

BrZnCH₂CO₂—R⁴   (VIII)

-   wherein R⁴ is a C₁-₆ alkyl group,

and then adding citric acid to the obtained reaction mixture.

Effect of the Invention

The production method of the present invention using, as organic metalreagents, an organic lithium compound and an organic magnesium compound,for the production of compound (VI) does not require the reaction to becarried out at an ultralow temperature (for example, −65° C.)

In addition, work-up of the reaction mixture by adding citric acid aftercompletion of the reaction in the production of compound (IX) suppressesdecomposition of compound (IX) as well as the amount of the zincremaining in the reaction mixture. As a result, the yield and purity ofcompound (IX) can be improved, and the yield and purity of the finalproduct,6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methy-1-2-naphthamideor a salt thereof, and the object product in each step up to the finalproduct can also be improved.

Accordingly, the production method of the present invention is a methodof producing6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-napht-hamideor a salt thereof, which is suitable for efficient and convenientindustrial production.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a powder X-ray diffraction pattern of6-((7S)-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-na-phthamide1 hydrate.

FIG. 2 shows a powder X-ray diffraction pattern of6-((7S)-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-na-phthamideanhydride.

DETAILED DESCRIPTION OF THE INVENTION

In the present specification, the “C₁₋₆ alkyl group” means methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl,1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl orthe like, and is preferably a C₁₋₄ alkyl group.

In the present specification, the “C₁₋₄ alkyl group” means methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl orthe like.

In the present specification, the “C₆₋₁₂ aryl group” means phenyl,1-naphthyl, 2-naphthyl or the like.

In the present specification, the “protecting group” means anitrogen-protecting group (e.g., a formyl group, a C₁₋₆ alkyl-carbonylgroup, a C₁₋₆ alkoxy-carbonyl group (e.g., tert-butoxycarbonyl), abenzoyl group, a C₇₋₁₀ aralkyl-carbonyl group (e.g., benzylcarbonyl), aC₇₋₁₄ aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,9-fluorenylmethoxycarbonyl), a trityl group, a phthaloyl group, anN,N-dimethylaminomethylene group, a substituted silyl group (e.g.,trimethylsilyl, triethylsilyl, dimethylphenylsilyl,tert-butyldimethylsilyl, tert-butyldiethylsilyl), a C₂₋₆ alkenyl group(e.g., 1-allyl), a substituted C₇₋₁₀ aralkyl group (e.g.,2,4-dimethoxybenzyl), a C₁₋₆ alkylsulfonyl group (e.g.,methanesulfonyl), a C₆₋₁₂ arylsulfonyl group (e.g., benzenesulfonyl,tosyl (toluenesulfonyl)), an N,N-di-C₁₋₆ alkylaminosulfonyl group (e.g.,N,N-dimethylaminosulfonyl) etc.). The protecting group is optionallysubstituted by 1 to 3 substituents selected from a halogen atom, a C₁₋₆alkoxy group and a nitro group.

R¹ is preferably a bromine atom.

R² is preferably a C₁₋₆ alkyl group, more preferably a C₁₋₄ alkyl group,more preferably isopropyl.

R^(2′) is preferably a C₁₋₆ alkyl group, more preferably a C₁₋₄ alkylgroup.

R³ is preferably a C₁₋₄ alkyl group, more preferably butyl.

R⁴ is preferably a C₁₋₄ alkyl group, more preferably ethyl.

X is preferably a chlorine atom.

PG is preferably trityl. In another embodiment, PG is preferably tosyl,benzenesulfonyl or N,N-dimethylaminosulfonyl.

Each step in the production method of the present invention is explainedin the following.

[Step 1]

In Step 1, compound (VI) is obtained by reacting compound (I) withcompound (II) or compound (III), and compound (IV), and then reactingthe resulting compound with compound (V).

First, compound (I) is reacted with compound (II) or compound (III), andcompound (IV) (Step 1a). Since the intermediate produced by the reactionhas a magnesiated methylamido group, and therefore, it is stabilized,and the next reaction with compound (V) can be carried out under a mildcondition.

Examples of the compound (II) include C₁₋₆ alkylmagnesium halides suchas methylmagnesium chloride, ethylmagnesium chloride, isopropylmagnesiumchloride, methylmagnesium bromide, ethylmagnesium bromide,isopropylmagnesium bromide and the like; and C₆₋₁₂ arylmagnesium halidessuch as phenylmagnesium chloride, phenylmagnesium bromide and the like.Among them, C₁₋₄ alkylmagnesium halides are preferable. The halide meanschloride, bromide or iodide, preferably chloride or bromide, morepreferably chloride. Compound (II) is preferably isopropylmagnesiumchloride.

Examples of the compound (III) include di-C₁₋₆ alkylmagnesiums. Amongthem, di-C₁₋₄ alkylmagnesiums are preferable. Compound (III) ispreferably dibutylmagnesium.

Examples of the compound (IV) include C₁₋₆ alkyllithiums such asn-butyllithium, sec-butyllithium, tert-butyllithium and the like; andC₆₋₁₂ aryllithiums. Among them, C₁₋₄ alkyllithiums are preferable.Compound (IV) is preferably n-butyllithium.

The amount of compound (II) or compound (III) to be used is generallyabout 0.1 to about 10 equivalents, preferably about 0.1 to about 3equivalents, relative to compound (I).

The amount of compound (IV) to be used is generally about 1 to about 10equivalents, preferably about 1 to about 3 equivalents, relative tocompound (I).

To improve the yield and purity of the object product, the reaction ispreferably carried out by adding (preferably adding dropwise) compound(II) or compound (III) to compound (I), and then adding (preferablyadding dropwise) compound (IV) to the obtained mixture.

The reaction is generally carried out in a solvent.

The solvent is not particularly limited as long as it does not adverselyinfluence the reaction, and examples thereof include aromatichydrocarbons such as benzene, toluene, xylene and the like; aliphatichydrocarbons such as hexane, pentane, heptane and the like; ethers suchas diethyl ether, diisopropyl ether, tert-butyl methyl ether,cyclopentyl methyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,bis(2-trimethoxyethyl)ether and the like; aromatic halogenatedhydrocarbons such as chlorobenzene, dichlorobenzene, benzotrifluorideand the like; and the like. These may be used alone or in a mixture oftwo or more kinds thereof at an appropriate ratio. Among them, theabove-mentioned ethers and aliphatic hydrocarbons are preferable, andtetrahydrofuran, hexane, heptane and toluene are more preferable.

The amount of the solvent to be used is generally 1 to 100-fold,preferably 10 to 80-fold, relative to compound (I).

The reaction temperature is generally about −40° C. to about 200° C.,preferably about −40° C. to about 40° C. When compound (II) or compound(III) is added to compound (I) and then compound (IV) is added to theobtained mixture, the addition of compound (II) or compound (III) isgenerally carried out at about −40° C. to about 200° C., preferablyabout −10° C. to about 40° C., and the addition of compound (IV) isgenerally carried out at −40° C. to about 200° C., preferably about −40°C. to about 10° C.

While the reaction time varies depending on the kinds of compound(I)-compound (IV) and the reaction temperature, it is generally about 5min to about 48 hr, preferably about 1 hr to about 12 hr.

After completion of the reaction, the reaction product is used for thenext reaction with compound (V) as the reaction mixture. Step 1a ispreferably carried out under an inert condition such as a nitrogenatmosphere and the like.

Compound (I)-compound (IV), which are starting materials, can beproduced according to a method known per se, for example, the methoddescribed in WO 03/059889.

Second, compound (VI) is obtained by reacting the reaction productobtained in Step 1a with compound (V) (Step 1b).

The amount of compound (V) to be used is generally about 0.1 to about 10equivalents, preferably about 1 to about 3 equivalents, relative tocompound (I).

The reaction is preferably carried out by adding (preferably addingdropwise) compound (V) to the reaction product obtained in Step 1a.

The reaction is generally carried out in a solvent. Examples of thesolvent include those similar to the solvent exemplified in Step 1a.

The reaction temperature is generally about −40° C. to about 200° C.,preferably about −40° C. to about 40° C.

While the reaction time varies depending on the kinds of compound (V)and the reaction temperature, it is generally about 5 min to about 48hr, preferably about 1 hr to about 12 hr.

After completion of the reaction, the obtained compound (VI) can be usedfor the next reaction as the reaction mixture or as a crude product, orcan also be isolated according to a conventional method from thereaction mixture, and can also be easily purified according to aconventional separation means (e.g., recrystallization, distillation,chromatography).

Compound (V) can be produced according to a method known per se.

[Step 2]

In Step 2, compound (VII) is obtained by subjecting compound (VI) tooxidation.

The oxidation is generally carried out using an oxidant in a solvent.

Examples of the oxidant include chromic acid-acetic acid, Jones reagent,anhydrous chromic acid-pyridine complex, manganese dioxide, silvercarbonate-Celite, dimethyl sulfoxide-oxalyl chloride, aluminumalkoxide-ketone, tetrapropylammonium-perruthenate, ruthenium tetraoxide,hypochlorous acid-acetic acid, periodinane compounds, dimethylsulfoxide-acetic anhydride,2,2,6,6-tetramethylpiperidine-1-oxyradical-hypochlorous acid,benzenesulfenamide-N-halogenated succinimide, N-halogenated succinimide,bromine, sodium hydride and the like. Among them, manganese dioxide andsodium hydride are preferable, and manganese dioxide is particularlypreferable.

The amount of the oxidant to be used is generally about 1 to about 30equivalents, preferably about 1 to about 10 equivalents, relative tocompound (VI).

The solvent is not particularly limited as long as it does not adverselyinfluence the reaction, and examples thereof include aromatichydrocarbons such as benzene, toluene, xylene and the like; aliphatichydrocarbons such as hexane, pentane, heptane and the like; esters suchas ethyl acetate, n-butyl acetate and the like; ethers such as diethylether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methylether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,bis(2-trimethoxyethyl)ether and the like; aliphatic halogenatedhydrocarbons such as dichloromethane, chloroform, dichloroethane, carbontetrachloride and the like; aromatic halogenated hydrocarbons such aschlorobenzene, dichlorobenzene, benzotrifluoride and the like; ketonessuch as acetone, methyl ethyl ketone and the like; and aprotic polarsolvents such as acetonitrile, N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide and thelike. These may be used alone or in a mixture of two or more kindsthereof at an appropriate ratio. Among them, the above-mentionedaliphatic halogenated hydrocarbons, ethyl acetate, N,N-dimethylformamideand N,N-dimethylacetamide are preferable.

The amount of the solvent to be used is generally 1 to 100-fold,preferably 5 to 80-fold, relative to compound (VI).

The reaction temperature is generally about −40° C. to about 200° C.,preferably about 0° C. to about 100° C.

While the reaction time varies depending on the kinds of compound (VI)and oxidant and the reaction temperature, it is generally about 5 min toabout 48 hr, preferably about 1 to about 12 hr.

After completion of the reaction, the resultant product can be used forthe next reaction as the reaction mixture or as a crude product, or canalso be isolated according to a conventional method from the reactionmixture, and can also be easily purified according to a conventionalseparation means (e.g., recrystallization, distillation,chromatography).

[Step 3]

In Step 3, compound (IX) is obtained by reacting compound (VII) withcompound (VIII).

Compound (VIII) is prepared from a compound represented by the formula:

BrCH₂CO₂—R⁴   (VIIIa)

-   wherein R⁴ is as defined above,-   (hereinafter sometimes to be referred to as compound (VIIIa)) and    zinc.

The preparation is generally carried out by reacting compound (VIIIa)with zinc in the presence of an activator, in a solvent.

The zinc is used in the form of powder, flake, wire or foil,particularly preferably in the form of powder. Zinc may be subjected toa conventional pre-treatment by washing with an acid, or a commerciallyavailable product may be directly used.

The amount of the zinc to be used is preferably an excess amountrelative to compound (VIIIa). Specifically, it is preferably 1equivalent or more, more preferably 1 to 50 equivalents, still morepreferably 1 to 5 equivalents, particularly preferably 1 to 3equivalents, relative to compound (VIIIa).

Examples of the activator include hydroiodic acid, 1,2-dibromoethane,halogenated copper, halogenated silver, trimethylsilyl chloride andmolecular sieve. Among them, trimethylsilyl chloride is preferable. Inaddition, zinc-copper couple, Rieke-Zn, zinc-silver-graphite, zincchloride-lithium, zinc chloride-lithium naphthalide, zinc and zinccompound each activated by ultrasonication, and the like can be used.

The amount of the activator to be used is generally about 0.01 to about1 equivalent, preferably about 0.01 to about 0.2 equivalent, relative tocompound (VIIIa).

To improve the yield and purity of the object product, the reaction ispreferably carried out by adding an activator to zinc, and then adding(preferably adding dropwise) compound (VIIIa) to the obtained mixture.

The solvent is not particularly limited as long as it does not adverselyinfluence the reaction, and examples thereof include aromatichydrocarbons such as benzene, toluene, xylene and the like; aliphatichydrocarbons such as hexane, pentane, heptane and the like; esters suchas ethyl acetate, butyl acetate and the like; ethers such as diethylether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran,dioxane, cyclopentyl methyl ether, 1,2-dimethoxyethane,bis(2-methoxyethyl)ether and the like; aliphatic halogenatedhydrocarbons such as methylene chloride, chloroform, dichloroethane,carbon tetrachloride and the like; aromatic halogenated hydrocarbonssuch as chlorobenzene, dichlorobenzene, benzotrifluoride and the like;and aprotic polar solvents such as acetonitrile, N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide and thelike. These may be used alone or in a mixture of two or more kindsthereof at an appropriate ratio. Among them, the above-mentionedaliphatic hydrocarbons, aromatic hydrocarbons and ethers are preferable,and cyclopentyl methyl ether and tetrahydrofuran are more preferable. Asmaller amount of water is preferably contained in the solvent, and theamount is particularly preferably 0.005% or less. When an ether such astetrahydrofuran and the like is used as a solvent, a stabilizer (e.g.,2,6-di-t-butyl-4-methyl-phenol etc.) may be added thereto if desired.

The amount of the solvent to be used is generally 1 to 100-fold,preferably 5 to 30-fold, relative to compound (VIIIa).

The addition of the activator is generally carried out at about −40° C.to about 100° C., preferably 0° C. to about 60° C. While the reactiontime varies depending on the kinds of the activator and the reactiontemperature, it is generally about 5 min to about 10 hr, preferablyabout 5 min to about 2 hr.

The addition of compound (VIIIa) is generally carried out at about −40°C. to about 100° C., preferably about 0° C. to about 60° C. While thereaction time varies depending on the kinds of compound (VIIIa) and thereaction temperature, it is generally about 5 min to about 10 hr,preferably about 5 min to about 2 hr.

Compound (VIIIa) can be produced according to a method known per se.

Compound (VIII) thus prepared is used for the next reaction withcompound (VII) as the reaction mixture.

The amount of compound (VIII) to be used is generally about 1 to about10 equivalents, preferably about 1 to about 5 equivalents, relative tocompound (VII).

In addition, an amine may be added to compound (VIII) in order topromote the reaction. Examples of the amine include aromatic amines suchas pyridine, lutidine, quinoline, bipyridyl and the like; and tertiaryamines such as triethylamine, tripropylamine, tributylamine,cyclohexyldimethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine,N,N′-tetramethylethylenediamine and the like.

The amount of the amine to be used is generally about 1 to about 20equivalents, preferably about 1 to about 10 equivalents, relative tocompound (VII).

The solvent is not particularly limited as long as it does not adverselyinfluence the reaction, and examples thereof include aromatichydrocarbons such as benzene, toluene, xylene and the like; aliphatichydrocarbons such as hexane, pentane, heptane and the like; esters suchas ethyl acetate, butyl acetate and the like; ethers such as diethylether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran,dioxane, cyclopentyl methyl ether, 1,2-dimethoxyethane,bis(2-methoxyethyl)ether and the like; aliphatic halogenatedhydrocarbons such as methylene chloride, chloroform, dichloroethane,carbon tetrachloride and the like; aromatic halogenated hydrocarbonssuch as chlorobenzene, dichlorobenzene, benzotrifluoride and the like;and aprotic polar solvents such as acetonitrile, N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide and thelike. These may be used alone or in a mixture of two or more kindsthereof at an appropriate ratio. Among them, the above-mentionedaliphatic hydrocarbons, aromatic hydrocarbons and ethers are preferable,and cyclopentyl methyl ether and tetrahydrofuran are more preferable.

The reaction temperature is generally about −80° C. to about 150° C.,preferably −40° C. to about 20° C.

While the reaction time varies depending on the kinds of compound (VII)and compound (VIII) and the reaction temperature, it is generally about5 min to about 20 hr, preferably about 30 min to about 5 hr.

After completion of the reaction, an acid is preferably added to thereaction mixture. The zinc which has been mixed up with compound (VIII)(the zinc which is remaining in the reaction mixture of compound (VIII))can be removed by the addition of the acid to the reaction mixture. Inaddition, compound (IX) can be obtained in high yield by the addition ofthe acid to the reaction mixture.

Examples of the acid include inorganic acids such as hydrochloric acid,hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and thelike; and organic acids such as formic acid, acetic acid,trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, malic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid andthe like. Among them, citric acid, tartaric acid, succinic acid, malicacid, fumaric acid and maleic acid are preferable, and citric acid isparticularly preferable, since the zinc which has been mixed up withcompound (VIII) can be efficiently removed and decomposition of thereaction product, compound (IX), can be prevented.

The amount of the acid to be used is generally about 1 to about100-fold, preferably about 5 to about 20-fold, relative to compound(VIII).

After the addition of the acid, the obtained compound (IX) can be usedfor the next reaction as the reaction mixture or as a crude product, orcan also be isolated according to a conventional method from thereaction mixture, and can also be easily purified according to aconventional separation means (e.g., recrystallization, distillation,chromatography).

The optically active compound (IX) can be obtained by reacting compound(VII) with compound (VIII) in the presence of an asymmetric ligand.

Examples of the asymmetric ligand include optically active aminoalcoholderivatives, optically active alcohol derivatives and optically activeamine derivatives. Examples of the optically active aminoalcoholderivative include cinchona alkaloids such as cinchonine, cinchonidine,quinidine, kinin and the like; N-methylephedrine, norephedrine,3-oxo-(dimethylamino)isoborneol, 1-methyl-2-pyrrolidinemethanol,1-benzyl-2-pyrrolidinemethanol,2-[hydroxy(diphenyl)methyl]-1-methylpyrrolidine and2,2′-{benzene-1,3-diylbis[methanediyl(methylimino)]}bis(1-phenylpropan-1-ol).Examples of the optically active alcohol derivative include1,2-binaphthol. Examples of the optically active amine derivativeinclude strychnine and sparteine. Compound (IX) having a desired stericconfiguration can be obtained depending on the selection of theasymmetric ligand.

The amount of the asymmetric ligand to be used is generally about 0.01to about 5 equivalents, preferably about 0.01 to about 2 equivalents,relative to compound (VII).

Step 3 can also be performed using compound (VIII) wherein the bromineatom is replaced by an iodine atom, instead of compound (VIII).

[Step 4]

In Step 4, compound (X) is obtained by subjecting compound (IX) toreduction.

The reaction is generally carried out in the presence of a metal hydridecomplex compound, in a solvent. A metal halide may be added for thisreaction.

Examples of the metal hydride complex compound include alkali metalhydride complex compounds such as sodium borohydride, lithiumborohydride, potassium borohydride, sodium cyanoborohydride and thelike; and zinc borohydride. Among them, alkali metal hydride complexcompounds such as sodium borohydride, lithium borohydride, potassiumborohydride and the like are preferable, sodium borohydride andpotassium borohydride are more preferable, and sodium borohydride isparticularly preferable.

The amount of the metal hydride complex compound to be used is generally1 to 50 mol, preferably 2 to 10 mol, per 1 mol of compound (IX).

Examples of the metal halide include halogenated aluminums such asaluminum chloride, aluminum bromide and the like; halogenated lithiumssuch as lithium iodide, lithium chloride, lithium bromide and the like;halogenated magnesiums such as magnesium chloride, magnesium bromide andthe like; halogenated calciums such as calcium chloride, calcium bromideand the like; halogenated zincs such as zinc chloride, zinc bromide andthe like; iron chloride, tin chloride and boron fluoride. Among them,halogenated calciums such as calcium chloride, calcium bromide and thelike; and halogenated zincs such as zinc chloride, zinc bromide and thelike are preferable, halogenated calciums such as calcium chloride,calcium bromide and the like are more preferable, and calcium chlorideis particularly preferable.

The amount of the metal halide to be used is generally 0.1 to 10 mol,preferably 0.1 to 5 mol, per 1 mol of compound (IX).

The solvent is not particularly limited as long as it does not adverselyinfluence the reaction, and examples thereof include aromatichydrocarbons such as benzene, toluene, xylene and the like; aliphatichydrocarbons such as hexane, pentane, heptane and the like; ethers suchas diethyl ether, diisopropyl ether, tert-butyl methyl ether,tetrahydrofuran, dioxane, 1,2-dimethoxyethane, bis(2-methoxyethyl)etherand the like; aliphatic halogenated hydrocarbons such as methylenechloride, chloroform, dichloroethane, carbon tetrachloride and the like;aromatic halogenated hydrocarbons such as chlorobenzene,dichlorobenzene, benzotrifluoride and the like; alcohols such asmethanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol,2-methyl-1-propanol and the like; and aprotic polar solvents such asacetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, dimethylsulfoxide and the like. These may be usedalone or in a mixture of two or more kinds thereof at an appropriateratio. Among them, the above-mentioned ethers and alcohols arepreferable, mixed solvents of ethers-alcohols are more preferable, and amixed solvent of tetrahydrofuran-ethanol, and a mixed solvent oftetrahydrofuran-methanol are particularly preferable.

The amount of the solvent to be used is 1 to 50-fold, preferably 10 to30-fold, relative to compound (IX).

The reaction temperature is generally about −80° C. to about 200° C.,preferably about −40° C. to about 40° C.

While the reaction time varies depending on the kinds of compound (IX),the metal hydride complex compound and metal halide and the reactiontemperature, it is generally about 5 min to about 48 hr, preferablyabout 3 to about 24 hr.

After completion of the reaction, the obtained compound (X) can be usedfor the next reaction as the reaction mixture or as a crude product, orcan also be isolated according to a conventional method from thereaction mixture, and can also be easily purified according to aconventional separation means (e.g., recrystallization, distillation,chromatography).

[Step 5]

In Step5,6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-nap-hthamideor a salt thereof is obtained by subjecting compound (X) to cyclizationand deprotection.

This reaction is generally carried out in a solvent, by (i) reactingcompound (X) with an agent for conversion of hydroxyl to a leavinggroup, and (ii) reacting the resulting compound with a base (cyclizationand deprotection).

The reactions of the above-mentioned (i) and (ii) may be carried outsimultaneously or stepwisely in no particular order.

Examples of the agent for conversion of hydroxyl to a leaving groupinclude halogenated sulfonyls such as methanesulfonyl chloride,p-toluenesulfonyl chloride and the like; and halogenating agents such ascarbon tetrachloride-triphenylphosphine,N-chlorosuccinimide-triphenylphosphine, thionyl chloride, lithiumchloride, carbon tetrabromide-triphenylphosphine,N-bromosuccinimide-triphenylphosphine, phosphorus tribromide, phosphorusbromide, sodium bromide, sodium iodide,imidazole-iodine-triphenylphosphine and the like. Among them,halogenated sulfonyls such as methanesulfonyl chloride,p-toluenesulfonyl chloride and the like are preferable, andmethanesulfonyl chloride is particularly preferable.

The amount of the agent for conversion of hydroxyl to a leaving group tobe used is generally 1 to 10 equivalents, preferably 1 to 5 equivalents,particularly preferably 1 to 2 equivalents, relative to compound (X).

Examples of the base include organic bases and inorganic bases. Examplesof the organic base include tertiary amines such as triethylamine,diisopropylethylamine, tri(n-propyl)amine, tri(n-butyl)amine,cyclohexyldimethylamine, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine and the like; and aromatic amines such as pyridine,lutidine, N,N-dimethylaniline and the like. Among them, tertiary aminessuch as triethylamine, diisopropylethylamine and the like arepreferable. Examples of the inorganic base include hydroxides of alkalimetal or alkaline earth metal such as sodium hydroxide, potassiumhydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide andthe like; carbonates of alkali metal or alkaline earth metal such assodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, potassium hydrogen carbonate and the like; and phosphatessuch as disodium monohydrogenphosphate, dipotassiummonohydrogenphosphate, trisodium phosphate, tripotassium phosphate andthe like. Among them, sodium carbonate and potassium hydrogen carbonateare preferable.

The amount of the base to be used is generally 0.1 to 10 equivalents,particularly preferably 1 to 2 equivalents, relative to compound (X).The base to be used may be alone or in combination of two or more. Forexample, when the base is used in combination of two or more, an aminemay be added in the reaction of compound (X) with an agent forconversion of hydroxyl to a leaving group, and an inorganic base may beadded in the reaction (cyclization and deprotection) of the resultantproduct by the above-mentioned reaction with the base presented in thereaction mixture.

The solvent is not particularly limited as long as it does not adverselyinfluence the reaction, and examples thereof include aromatichydrocarbons such as benzene, toluene, xylene and the like; aliphatichydrocarbons such as hexane, pentane, heptane and the like; ethers suchas diethyl ether, diisopropyl ether, tert-butyl methyl ether,cyclopentyl methyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,bis(2-methoxyethyl)ether and the like; aliphatic halogenatedhydrocarbons such as methylene chloride, chloroform, dichloroethane,carbon tetrachloride and the like; aromatic halogenated hydrocarbonssuch as chlorobenzene, dichlorobenzene, benzotrifluoride and the like;alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol,2-butanol, 2-methyl-1-propanol and the like; aprotic polar solvents suchas acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, dimethylsulfoxide and the like; and water. Thesemay be used alone or in a mixture of two or more kinds thereof at anappropriate ratio. Among them, the above-mentioned aromatichydrocarbons, ethers, aprotic polar solvents and water are preferable,toluene, tetrahydrofuran, acetonitrile and water are more preferable,tetrahydrofuran, methanol, acetonitrile and water are still morepreferable, and a mixed solvent of tetrahydrofuran-water is particularlypreferable.

The amount of the solvent to be used is 1 to 50-fold, preferably 5 to30-fold, relative to compound (X).

After completion of the reaction, the obtained6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-napht-hamidecan be isolated according to a conventional method from the reactionmixture, and can also be easily purified according to a conventionalseparation means (e.g., recrystallization, distillation,chromatography). For example, the purification is performed bydissolving the crude product in water-methanol, and adding dropwisewater to the obtained solution under cooling.

In the present specification,6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-napht-hamideencompasses6-((7S)-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-na-phthamideand6-((7R)-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide.

6-(7-Hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamidemay be in the form of a salt, preferably a pharmacologically acceptablesalt. Examples of the salt include salts with an inorganic base, saltswith an organic base, salts with an inorganic acid, salts with anorganic acid, and salts with a basic or acidic amino acid.

Preferable examples of the salts with an inorganic base include alkalimetal salts such as sodium salt, potassium salt and the like; alkalineearth metal salts such as calcium salt, magnesium salt and the like; analuminum salt; and an ammonium salt.

Preferable examples of the salts with an organic base include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine,tromethamine[tris(hydroxymethyl)methylamine], tert-butylamine,cyclohexylamine, benzylamine, dicyclohexylamine orN,N-dibenzylethylenediamine.

Preferable examples of the salts with an inorganic acid include saltswith hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid orphosphoric acid.

Preferable examples of the salts with an organic acid include salts withformic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaricacid, oxalic acid, tartaric acid, maleic acid, citric acid, succinicacid, malic acid, methanesulfonic acid, benzenesulfonic acid orp-toluenesulfonic acid.

Preferable examples of the salts with a basic amino acid include saltswith arginine, lysine or ornithine.

Preferable examples of the salts with an acidic amino acid include saltswith aspartic acid or glutamic acid.

In the present specification,6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamidemay be in the form of a hydrate or non-hydrate. These are encompassed in6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide.

Compound (V), compound (VI), compound (VII), compound (IX) and compound(X) may be in the form of a salt, and examples thereof include thosesimilar to the salts of6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide.

6-(7-Hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamideor a salt thereof obtained according the production method of thepresent invention can be used as an agent for the prophylaxis ortreatment of androgen-independent prostate cancer and the like,according the method described in WO 2009/057795 and the like.

EXAMPLES

The present invention is explained in detail in the following byreferring to Reference Examples and Examples, which are not to beconstrued as limitative.

In Reference Examples and Examples, the room temperature means about 25°C.

Reference Example 1

To 4-formylimidazole (30.0 g, 0.30 mol) were added toluene (300 mL) andtriethylamine (35.0 g, 0.34 mol), and then N,N-dimethylaminosulfonylchloride (50.0 g, 0.34 mol) was added thereto at room temperature. Themixture was stirred at 70° C. for 20 hr, and the insoluble material wascollected by filtration, and washed with toluene (300 mL) to give wetcrystals. To the obtained wet crystals were added water (100 mL) andethyl acetate (300 mL), and the crystals were dissolved with stirring atroom temperature. The organic layer and the aqueous layer wereseparated. The obtained aqueous layer was extracted with ethyl acetate(200 mL), and the organic layer and the aqueous layer were separated.The obtained organic layer and the previously obtained organic layerwere combined. These operations were repeated twice, and the organiclayer was completely concentrated under reduced pressure to give crudecrystals (32.0 g). To the crude crystals was added ethyl acetate (90mL), and crystals were dissolved with heating to about 60° C. Thesolution was slowly cooled to 30° C. for recrystallization, hexane (180mL) was added thereto, and the mixture was stirred at room temperaturefor 2 hr to give crystals. The obtained crystals were collected byfiltration, and washed with a mixed solvent (45 mL) of ethylacetate/hexane (1:2, volume ratio). The obtained wet crystals were driedunder reduced pressure to give1-N,N-dimethylaminosulfonyl-4-formyl-1H-imidazole (29.4 g, 0.14 mmol).yield 48%

¹H NMR (500 MHz, DMSO-d₆) δ 2.93 (s, 6H), 7.90 (d, J=1.3 Hz, 1H), 7.96(d, J=1.3 Hz, 1H), 9.95 (s, 1H)); HRMS (ESI) m/z Calcd for aC₆H₁₀N₃O₃S[m+H]⁺: 204.0365. Found: 204.0438.

Reference Example 2

4-Formylimidazole (20.0 g, 208.14 mmol) and p-toluenesulfonyl chloride(43.7 g, 229.0 mmol) were suspended in N,N-dimethylacetamide (200 mL).To the obtained suspension was added dropwise triethylamine (23.2 g,229.0 mmol) at 10° C. or below, and the mixture was stirred at 10° C. orbelow for 1 hr or more. To the reaction mixture was added n-heptane (60mL) at 30° C. or below. To the obtained solution was added dropwisewater (240 mL) at 30° C. or below for crystallization. The mixture wasstirred at room temperature for 1 hr or more to give crystals. Theobtained crystals were collected by filtration, and washed with water(300 mL) to give wet crystals. The obtained wet crystals were driedunder reduced pressure at an outside temperature of 50° C. to give1-tosyl-4-formyl-1H-imidazole (44.2 g, 176.6 mmol). yield 85%. ¹H NMR(500 MHz, DMSO-d₆) δ 2.42 (s, 1H), 7.54-7.56 (m, 2H), 8.06-8.08 (m, 2H),8.58 (s, 1H), 8.66 (s, 1H), 9.76 (s, 1H).

Reference Example 3

4-Formylimidazole (11.7 g, 121.8 mmol) and acetonitrile (59 mL) werecharged, and triethylamine (13.6 g, 133.9 mml) was added thereto at 30°C. or below. And then, a solution of benzenesulfonyl chloride (23.7 g,133.9 mmol) in THF (35 mL) was added dropwise thereto at 30° C. orbelow, and the mixture was stirred at room temperature for 1 hr or more.After the reaction, water (94 mL) was added dropwise thereto at 30° C.or below for crystallization, and the mixture was stirred at roomtemperature for 1 hr or more, cooled to 10° C. or below, and stirred for1 hr or more. The obtained crystals were collected by filtration, andwashed with a mixed solvent (35 mL) of acetonitrile/water (1:2, volumeratio). The obtained wet crystals were dried under reduced pressure atan outside temperature of 50° C. to give1-(phenylsulfonyl)-4-formyl-1H-imidazole (20.0 g, 84.7 mmol). yield 70%.

¹H NMR (500 MHz, DMSO-d₆) δ 7.74-7.77 (m, 2H), 7.88-7.89 (m, 1H),8.19-8.21 (m, 2H), 8.62 (s, 1H), 8.70 (d, J=5.0 Hz, 1H), 9.76 (s, 1H);HRMS (ESI) m/z Calcd for a C₁₀H₉N₂O₃S[M+H]⁺: 237.0289. Found: 237.0330.

Reference Example 4

To a solution of 4-formylimidazole (10.0 g, 104.1 mmol) intetrahydrofuran (100 mL) were added triethylamine (12.6 g, 124.9 mmol)and a catalytic amount of 4-dimethylaminopyridine (2.5 g, 20.8 mmol). Asolution of di-t-butyl-dicarbonate (27.3 g, 124.9 mmol) in THF (50 mL)was added dropwise thereto at 30° C. or below, and the mixture wasstirred at room temperature for 1 hr or more. After the reaction, water(100 mL) was added dropwise thereto at 30° C. or below to quench thereaction, and the ethyl acetate (200 mL) was added thereto. The organiclayer was separated, and concentrated under reduced pressure to thevolume of about 30 mL. To the residue was added diisopropyl ether (100mL), and the mixture was concentrated to the volume of about 20 mL underreduced pressure. These operations were repeated twice to adjust thevolume to about 20 mL. The crystals were collected by filtration, andwashed with diisopropyl ether (20 mL), and then washed twice with water(50 mL). The obtained wet crystals were dried under reduced pressure atan outside temperature of 50° C. to give t-butyl4-formyl-1H-imidazole-1-carboxylate (16.0 g, 81.5 mmol). yield 78%.

¹H NMR (500 MHz, DMSO-d₆) δ 1.60 (s, 9H), 8.37-8.39 (m, 2H), 9.81 (s,1H).

Reference Example 5

6-(7-Hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide(5.20 kg, 16.9 mol), ethanol (130 L) and activated carbon (260 g) werestirred at room temperature, and the insoluble material was filteredoff, and washed with ethanol (15.6 L). The above-mentioned operationswere repeated three times. The filtrates and washings were combined, and(2S,3S)-tartranilic acid (15.95 kg, 70.8 mol) and ethanol (20.8 L) wereadded thereto. The mixture was heated to about 50° C., allowed to coolto room temperature, stirred for about 4 hr, cooled to about 0° C., andstirred for about 1 hr. The precipitated crystals were collected byfiltration, and washed with ethanol (31.2 L). The obtained wet crystals(about 23 kg) in ethanol (156 L) were stirred at room temperature forabout 2 hr, and the mixture was cooled to about 0° C., and stirred forabout 1 hr. The precipitated crystals were collected by filtration, andwashed with ethanol (31.2 L). The obtained wet crystals (about 20 kg)were added to 1 mol/L aqueous sodium hydroxide solution (104 L), and themixture was stirred at room temperature for about 1 hr. The precipitatedcrystals were collected by filtration, washed with water (93.6 L), anddried under reduced pressure to a constant amount to give6-(7S)-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-na-phthamide1 hydrate (4.11 kg, 12.6 mol). yield 25%. containing 5.6 wt % water (byKarl-Fisher water measurement).

The powder X-ray diffraction pattern of6-((7S)-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide1 hydrate is shown in FIG. 1.

Reference Example 6

6-(7S)-Hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methy-1-2-naphthamide1 hydrate (4.05 kg, 12.4 mol) was added to 60% aqueous methanol solution(118 L), and dissolved with heating to about 70° C. Activated carbon(203 g) was added thereto at the same temperature, and the insolublematerial was filtered off, and washed with 60% aqueous methanol solution(11.6 L). The filtrate and washing were combined, and heated to about73° C. to dissolve the precipitated crystals, the solution was cooled toabout 55° C., and water (25.9 L) was added thereto. While cooling, themixture was stirred at room temperature for about 1 hr, and then atabout 0° C. for about 2 hr. The precipitated crystals were collected byfiltration, washed with 50% aqueous methanol solution (12.2 L), anddried under reduced pressure to a constant amount to give6-(7S)-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamideanhydride (3.13 kg, 10.2 mol). yield 82%.

The powder X-ray diffraction pattern of6-((7S)-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamideanhydride is shown in FIG. 2.

Reference Example 7

6-Bromo-2-naphthoic acid (10.1 g, 40.1 mmol) and N,N-dimethylformamide(4.75 g, 65.0 mmol) were added to toluene (80 mL). To the reactionmixture was added dropwise thionyl chloride (5.7 g, 48.2 mmol) at 45 to50° C., and the mixture was stirred for 1 hr, and allowed to cool toroom temperature. The reaction mixture was added dropwise at 10 to 25°C. to a solution prepared by adding triethylamine (11.4 g, 112.4 mmol)and 40% methylamine methanol solution (8.1 g, 104.4 mmol) to toluene (80mL), and the mixture was stirred at room temperature for 1 hr. To thereaction mixture was added dropwise water (50 mL), and the mixture wasstirred at room temperature. The crystals were collected by filtration,and washed with a mixed solvent (25 mL) of methanol/water (2:8) to givewet crystals. The total amount of the wet crystals was added toN,N-dimethylacetamide (70 mL), and dissolved with heating to 60° C. Thereaction mixture was allowed to cool to room temperature, and water (140mL) was added dropwise thereto. The crystals were collected byfiltration, and washed with water (80 mL) to give wet crystals. Thetotal amount of the wet crystals was suspended in ethyl acetate (25 mL)with stirring at room temperature. The crystals were collected byfiltration, and washed with ethyl acetate (5 mL). The obtained wetcrystals were dried under reduced pressure to give6-bromo-N-methyl-2-naphthamide (9.4 g, 35.6 mmol). yield 89%.

¹H NMR (500 MHz, DMSO-d₆) δ 2.84 (d, J=4.4 Hz, 3H), 7.71 (dd, J=8.8, 2.2Hz, 1H), 7.93-8.03 (m, 3H), 8.28 (d, J=1.9 Hz, 1H), 8.44 (s, 1H), 8.62(d, J=4.1 Hz, 1H); HRMS (ESI) m/z Calcd for a C₁₂H₁₁NOBr [M+H]⁺:264.0024. Found: 264.0019; Anal. Calcd for a C₁₂H₁₀NOBr: C, 54.57; H,3.82; N, 5.30; Br, 30.25. Found: C, 54.56; H, 3.70; N, 5.34; Br, 30.23.

Reference Example 8

Under a nitrogen atmosphere, o-bromotrifluoromethylbenzene (1.35 kg,6.00 mol) was added to tetrahydrofuran (7.9 L). The reaction mixture wascooled to −70° C., 1.6 mol/L n-butyllithium hexane solution (3.75 L,6.00 mol) was added dropwise thereto, and the mixture was stirred at thesame temperature for about 30 min. The reaction mixture was addeddropwise at the same temperature to a solution prepared by adding6-bromo-N-methyl-2-naphthamide (1.13 kg, 4.28 mol) to THF (62.2 L) at−70° C. under a nitrogen atmosphere, and the mixture was stirred for 1.5hr. To the reaction mixture were added dropwise successively 1.6 mol/Ln-butyllithium hexane solution (2.67 L, 4.27 mol) and a solution of1-trityl-4-formyl-1H-imidazole (1.21 kg, 3.58 mol) in THF (7.9 L) at thesame temperature, and the mixture was stirred for 2 hr. The reactionmixture was allowed to warm to −10° C., and 20 w/v % aqueous ammoniumchloride solution (17.0 L) was added dropwise thereto at −10 to 0° C.The separated organic layer was concentrated under reduced pressure. Tothe residue was added ethyl acetate (11.3 L), and the mixture wasstirred at room temperature. The crystals were collected by filtration,and washed with ethyl acetate (11.3 L). The obtained wet crystals weredried under reduced pressure to give6-[hydroxy(1-trityl-1H-imidazol-4-yl)methyl]-N-methyl-2-naphthamide(1.31 kg, 2.50 mol). yield 58%.

Reference Example 9

To glucosamine hydrochloride (200 g, 0.928 mol) were added water (300mL) and ammonium thiocyanate (212 g, 2.78 mol, 3.0 equivalents) at 25°C., and the mixture was stirred at 80 to 89° C. for 8 hr. The reactionmixture was allowed to cool to 60° C., water (300 mL) and seed crystalswere added thereto, and the mixture was stirred at 25 to 40° C. for 15hr. The crystals were collected by filtration, washed twice with water(100 mL), and vacuum-dried (50° C.) to a constant amount to give(1R,2S,3R)-1-(2-sulfanyl-1H-imidazol-4-yl)butane-1,2,3,4-tetraol (101.4g). yield 50%.

Reference Example 10

Under nitrogen stream, to(1R,2S,3R)-1-(2-sulfanyl-1H-imidazol-4-yl)butane-1,2,3,4-tetraol (10 g,45.4 mmol) was added water (40 mL), and to the obtained suspension wasadded dropwise an aqueous diluted solution of 30% aqueous hydrogenperoxide (15.4 g, 136 mmol, 3.0 equivalents) in water (40 mL) over 10min at 17 to 43° C. (the compound was gradually dissolved to give anuniform pale-yellow solution). The reaction mixture was stirred at 24 to36° C. for 4 hr, and barium carbonate (27 g, 136 mmol, 3.0 equivalents)was added over 5 min at 24 to 26° C. (neutralized to pH 7), and themixture was stirred at 25 to 26° C. for 1 hr and 20 min. The insolublematerial was filtered off, and washed with water (40 mL). To thefiltrate and washing was added sodium sulfite (11.4 g, 90.8 mmol, 2.0equivalents) over 5 min at 20 to 32° C. The obtained aqueous solutionwas stirred at 26 to 32° C. for 1 hr and 30 min to give an aqueoussolution of (1R,2S,3R)-1-(1H-imidazol-4-yl)butane-1,2,3,4-tetraol. Tothis aqueous solution was added sodium periodate (29.1 g, 136 mmol, 3.0equivalents) over 10 min at 12 to 30° C., and the mixture was stirred at27 to 30° C. for 1 hr and 30 min. To the reaction mixture was addedsodium periodate (2.91 g, 13.6 mmol, 0.3 equivalents) at 27 to 30° C.,and the mixture was stirred at 27 to 30° C. for 2 hr. The insolublematerial was filtered off, and washed four times with water (10 mL). Tothe filtrate and washing was added methanol (500 mL), and the inorganicsalt was filtered off, and washed twice with methanol (50 mL). To thefiltrate and washing was added activated carbon (3 g, SHIRASAGI A, tradename), and the mixture was stirred at room temperature for 1 hr. Theinsoluble material was filtered off, and washed with methanol. Thefiltrate and washing were concentrated under reduced pressure to give acrude compound (9.37 g). To the crude compound were added water (3 mL)and seed crystals for crystallization, and the mixture was stirred atroom temperature for 24 hr, and then for 2 hr under ice-cooling. Thecrystals were collected by filtration, washed with cooled water (1 mL),and vacuum-dried (50° C.) to a constant amount to give4(5)-formylimidazole (2.35 g). yield 54%.

Reference Example 11

To 4(5)-formylimidazole (2 g, 20.8 mmol) were added DMAc (30 mL) andtriethylamine (3.5 mL, 25.0 mmol, 1.2 equivalents), and then tritylchloride (4.06 g, 14.6 mmol, 0.7 equivalents) was added thereto at roomtemperature. The mixture was stirred at room temperature for 24 hr, andto the reaction mixture was added water (60 mL) at room temperature, andthe mixture was stirred at room temperature for 2 hr. The crystals werecollected by filtration, washed with water, and vacuum-dried (50° C.) toa constant amount to give a crude compound (4.6 g). To the crudecompound (0.2 g) was added methanol (1 mL), and the mixture was stirredat room temperature for 2 hr. The crystals were collected by filtration,was washed with methanol (0.2 mL), and vacuum-dried (50° C.) to aconstant amount to give 1-trityl-4-formyl-1H-imidazole (0.14 g). yield65%.

Example 1

Under a nitrogen atmosphere, 6-bromo-N-methyl-2-naphthamide (7.0 g, 26.5mmol) was added to tetrahydrofuran (175 mL), and then 2.0 mol/Lisopropylmagnesium chloride tetrahydrofuran solution (13.7 mL) was addeddropwise thereto at room temperature. The reaction mixture was cooled to−30° C., 1.6 mol/L n-butyllithium hexane solution (26.6 mL) was addeddropwise thereto, and the mixture was stirred at the same temperaturefor 2 hr. To the reaction mixture was added dropwise a solution of1-trityl-4-formyl-1H-imidazole (13.5 g, 39.9 mmol) in tetrahydrofuran(140 mL) at −20° C., and the mixture was stirred at the same temperaturefor 2 hr. The reaction mixture was allowed to warm to 0° C., and stirredfor 1 hr, and 20 w/v % aqueous ammonium chloride solution (105 mL) wasadded dropwise thereto. The organic layer was separated, andconcentrated to the volume of about 90 mL under reduced pressure. To theresidue was added tetrahydrofuran (140 mL), and the mixture wasconcentrated to the volume of about 90 mL under reduced pressure. To theresidue was added acetone (140 mL), and the mixture was concentrated tothe volume of about 140 mL under reduced pressure. These operations wererepeated three times. To the residue was added acetone to adjust thevolume to about 180 mL, and the mixture was stirred at room temperature.The crystals were collected by filtration, and washed with acetone (70mL). The obtained wet crystals were dried under reduced pressure to give6-[hydroxy(1-trityl-1H-imidazol-4-yl)methyl]-N-methyl-2-naphthamide(10.3 g, 19.7 mmol). yield 74%.

¹H NMR (500 MHz, DMSO-d₆) δ 2.84 (d, J=4.7 Hz, 3H), 5.76 (d, J=5.0 Hz,1H), 5.82 (d, J=4.7 Hz, 1H), 6.80 (s, 1H), 6.98-7.13 (m, 6H), 7.28 (d,J=1.6 Hz, 1H), 7.32-7.50 (m, 9H), 7.55 (dd, J=8.5, 1.6 Hz, 1H),7.83-7.99 (m, 4H) 8.37 (s, 1H) 8.58 (d, J=4.4 Hz, 1H); HRMS (ESI) m/zCalcd for a C₃₅H₃₀N₃O₂[M+H] 524.2338. Found: 524.2325; Anal. Calcd for aC₃₅H₂₉N₃O₂: C, 80.28; H, 5.58; N, 8.02. Found: C, 80.17; H, 5.80; N,7.81.

Example 2

Under a nitrogen atmosphere, 6-bromo-N-methyl-2-naphthamide (1.0 g, 3.79mmol) was added to tetrahydrofuran (25 mL), and then 1.0 mol/Ldibutylmagnesium heptane solution (2.0 mL) was added dropwise thereto atroom temperature. The obtained solution was cooled to −13° C., 1.6 mol/Ln-butyllithium hexane solution (2.6 mL) was added dropwise thereto, andthe mixture was stirred at the same temperature for 1.5 hr. A solutionof 1-trityl-4-formyl-1H-imidazole (1.4 g, 4.2 mmol) in tetrahydrofuran(15 mL) was added dropwise to the reaction mixture at −11° C., and themixture was stirred at the same temperature for 5 hr. The reactionmixture was allowed to warm to 6° C. over 2.5 hr, and 20 w/v % aqueousammonium chloride solution (30 mL) was added dropwise thereto. Theorganic layer was separated, and quantified to give6-[hydroxy(1-trityl-1H-imidazol-4-yl)methyl]-N-methyl-2-naphthamide (1.2g, 2.24 mmol). yield 71%.

Example 3

6-[Hydroxy(1-trityl-1H-imidazol-4-yl)methyl]-N-methyl-2-naphthamide(10.0 g, 19.1 mmol) and manganese dioxide (10.0 g, 115.0 mmol) wereadded to a mixed solvent of N,N-dimethylacetamide (25 mL) and ethylacetate (63 mL), and the mixture was stirred at 60° C. for 3 hr. Theinsoluble material was filtered off at the same temperature, and washedwith ethyl acetate (60 mL). The filtrate and washing were combined andconcentrated to the volume of 30 mL under reduced pressure. To theresidue was added dropwise diisopropyl ether (100 mL), and the mixturewas stirred at room temperature. The obtained crystals were collected byfiltration, and washed with diisopropyl ether (30 mL) to give crude wetcrystals (26.4 g). The crude wet crystals (10.8 g) were added to ethylacetate (54 mL), and the mixture was warmed to 60° C., and stirred for0.5 hr. The obtained mixture was allowed to cool to room temperature,and diisopropyl ether (108 mL) was added dropwise thereto. The mixturewas stirred with cooling to 5° C. The obtained crystals were collectedby filtration, and washed with a mixed solvent (27 mL) of diisopropylether/ethyl acetate (2:1, volume ratio). The obtained wet crystals weredried under reduced pressure to giveN-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (8.2 g,15.7 mmol). yield 82%.

¹H NMR (500 MHz, DMSO-d₆) δ 2.85 (d, J=4.7 Hz, 3H), 7.17-7.22 (m, 6H),7.40-7.50 (m, 9H), 7.69 (d, J=1.4 Hz, 1H), 7.77 (d, J=1.4 Hz, 1H), 7.99(dd, J=8.5, 1.6 Hz, 1H), 8.13 (dd, J=18.4, 8.7 Hz, 2H), 8.21 (dd, J=8.5,1.6 Hz, 1H), 8.48 (s, 1H), 8.68 (q, J=4.4 Hz, 1H), 9.01 (s, 1H); HRMS(ESI) m/z Calcd for a C₃₅H₂₈N₃O₂[M+H] 522.2182. Found: 522.2177; Anal.Calcd for a C₃₅H₂₇N₃O₂: C, 80.59; H, 5.22; N, 8.06. Found: C, 80.51; H,5.17, N, 8.10.

Example 4

6-[Hydroxy(1-trityl-1H-imidazol-4-yl)methyl]-N-methyl-2-naphthamide(10.0 g, 19.1 mmol) and manganese dioxide (6.6 g, 75.9 mmol) were addedto N,N-dimethylacetamide (85 mL), and the mixture was stirred at 60° C.for 2 hr. The insoluble material was filtered off at the sametemperature, and washed with N,N-dimethylacetamide (40 mL). The filtrateand washing were combined and cooled to 40° C., water (60 mL) was addeddropwise thereto, and the mixture was stirred at room temperature. Theobtained crystals were collected by filtration, and washed with water(50 mL). The wet crystals were dried under reduced pressure to givecrude crystals (9.5 g). Ethyl acetate (100 mL) was warmed to 40° C., andthe crude crystals (9.5 g) were added thereto. The obtained mixture waswarmed to 50° C., and stirred for 0.5 hr. The solvent (20 mL) wasevaporated under reduced pressure. The residue was allowed to cool toroom temperature, and diisopropyl ether (80 mL) was added dropwisethereto, and the mixture was stirred at the same temperature. Theobtained crystals were collected by filtration, and washed with a mixedsolvent (30 mL) of diisopropyl ether/ethyl acetate (1:1, volume ratio).The obtained wet crystals were dried under reduced pressure to giveN-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (8.9 g,17.1 mmol). yield 89%.

Example 5

Under a nitrogen atmosphere,6-[hydroxy(1-trityl-1H-imidazol-4-yl)methyl]-N-methyl-2-naphthamide (1.0g, 1.91 mmol) was added to N,N-dimethylacetamide (50 mL), and thensodium hydride (oil, 0.15 g, 3.85 mmol) was added at room temperature,and the mixture was stirred at the same temperature for about 60 hr. Tothe reaction mixture were added dropwise water (50 mL) and 1 mol/Lhydrochloric acid (5 mL) at room temperature, and the mixture wasstirred at the same temperature for 45 min. Then, the reaction mixturewas cooled to 0° C., and stirred for 2 hr. The crystals were collectedby filtration, and washed with water (30 mL). The obtained wet crystalswere dried under reduced pressure to giveN-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (0.89 g,1.71 mmol). yield 90%.

Example 6

Under a nitrogen atmosphere, zinc powder (15.0 g, 229.4 mmol) wassuspended in tetrahydrofuran (57 mL), trimethylsilyl chloride (1.5 mL,11.5 mmol) was added thereto at room temperature, and the mixture wasstirred for 30 min. The reaction mixture was heated to 40° C., asolution of ethyl bromoacetate (12.7 mL, 114.5 mmol) in tetrahydrofuran(144 mL) was added dropwise thereto, and the mixture was stirred at thesame temperature for 30 min. The reaction mixture was kept stand at roomtemperature, the excess amount of zinc was filtered off to give areaction mixture containing (bromo(2-ethoxy-2-oxoethyl)zinc (hereinafterto be abbreviated as Reformatsky reagent). The prepared Reformatskyreagent (89.6 mL, corresponding to 2.5 eq.) was cooled to 0° C.,cinchonine (7.1 g, 24.0 mmol), pyridine (6.2 mL, 76.8 mmol) andtetrahydrofuran (80 mL) were added thereto, and the mixture was stirredat the same temperature for 30 min. The reaction mixture was cooled to−25° C., N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide(10.0 g, 19.2 mmol) and tetrahydrofuran (20 mL) were added thereto, andthe mixture was stirred at the same temperature for 1 hr and 45 min. TheReformatsky reagent (35.7 mL, corresponding to 1.0 eq.) was addedthereto at the same temperature, and the mixture was stirred for 1 hr.To the reaction mixture were added ethyl acetate (140 mL) and 20 w/v %aqueous citric acid solution (140 mL) at 10° C. or below. The organiclayer was separated, and washed with 10% sodium chloride-containing 20w/v % aqueous citric acid solution (100 mL) at 5° C. (twice), 5 w/v %aqueous sodium bicarbonate (100 mL) (three times), and water (100 mL).The organic layer was concentrated to the volume of 60 mL under reducedpressure. To the residue was added methanol (100 mL), and the mixturewas concentrated to the volume of 60 mL under reduced pressure. To theresidue was added methanol to adjust the volume to 200 mL. Water (20 mL)was added thereto at room temperature, and the mixture was stirred for 1hr. Then water (140 mL) was added dropwise thereto at the sametemperature, and the mixture was stirred. The obtained crystals werecollected by filtration, and washed with a mixed solvent (60 mL) ofmethanol/water (1:3, volume ratio). The obtained wet crystals were driedunder reduced pressure to giveethyl(3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-im-idazol-4-yl)propanoate(11.3 g, 18.5 mmol). yield: 97%. enantiomeric excess: 96% ee.

¹H NMR (500 MHz, DMSO-d₆) δ 0.93 (t, J=7.1 Hz, 3H), 2.84 (d, J=4.4 Hz,3H), 3.20 (d, J=14.2 Hz, 1H), 3.29 (d, J=14.5 Hz, 1H), 3.86 (t, J=6.9Hz, 2H), 5.86 (s, 1H), 6.79 (d, J=1.6 Hz, 1H), 7.06 (dd, J=7.9, 1.9 Hz,6H), 7.31 (d, J=1.3 Hz, 1H), 7.33-7.45 (m, 9H), 7.73 (dd, J=8.7, 1.7 Hz,1H), 7.82-7.95 (m, 3H), 8.02 (s, 1H), 8.36 (s, 1H), 8.58 (q, J=4.7 Hz,1H); HRMS (ESI) m/z Calcd for a C₃₉H₃₆N₃O₄ [M+H]⁺: 610.2706. Found:610.2698; Anal. Calcd for a C₃₉H₃₆N₃O₄: C, 76.83; H, 5.79; N, 6.89.Found: C, 76.79; H, 5.95; N, 6.81.

Example 7

To a solution of anhydrous calcium chloride (4.55 g, 41.0 mmol) inethanol (62.5 mL) was added sodium borohydride (3.11 g, 82.0 mmol) at−7° C., and the mixture was stirred at −7° C. for 30 min. To thereaction mixture were added dropwise a solution ofethyl(3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-im-idazol-4-yl)propanoate(10.0 g, 16.4 mmol) in tetrahydrofuran (80 mL), and tetrahydrofuran (20mL) at −5° C. The reaction mixture was stirred at 5° C. for 8 hr, water(80 mL), 1 mol/L hydrochloric acid (82 mL) and ethyl acetate (200 mL)were added dropwise thereto at 5° C., and the mixture was stirred. Tothe separated organic layer was added 0.2 mol/L hydrochloric acid (82mL) at 5° C., and the mixture was stirred, and adjusted to pH 7.5 with0.5 mol/L aqueous sodium hydroxide solution at the same temperature. Tothe separated organic layer was added again 0.2 mol/L hydrochloric acid(82 mL) at 5° C., and the mixture was stirred, and adjusted to pH 7.5with 0.5 mol/L aqueous sodium hydroxide solution at the sametemperature. To the separated organic layer was added water (100 mL),and the mixture was adjusted to pH 9.5 with 0.5 mol/L aqueous sodiumhydroxide solution. The separated organic layer was washed with 10 w/v %brine (100 mL). To the separated organic layer was added water (120 mL),and the mixture was stirred with heating to 60° C. for 4 hr. Theseparated organic layer was concentrated to the volume of about 38 mL atthe same temperature under reduced pressure. To the residue was addedethyl acetate (80 mL), and the mixture was concentrated to the volume ofabout 38 mL under reduced pressure. These operations were repeated threetimes. To the residue was added ethyl acetate to adjust the volume toabout 38 mL. Diisopropyl ether (75 mL) was added thereto, and themixture was stirred with cooling to 5.degree. C. The crystals werecollected by filtration, and washed with a mixed solvent (30 mL) ofdiisopropyl ether/ethyl acetate (2:1, volume ratio). The obtained wetcrystals were dried under reduced pressure to give6-[(1S)-1,3-dihydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide(8.7 g, 15.3 mmol). yield 94%. enantiomeric excess: 94% ee.

¹H NMR (500 MHz, DMSO-d₆) δ 2.19-2.35 (m, 1H), 2.40-2.49 (m, 1H), 2.83(d, J=4.7 Hz, 3H), 3.38 (ddd, J=19.2, 8.8, 5.4 Hz, 2H), 4.47 (t, J=5.0Hz, 1H), 5.7 (s, 1H), 6.9 (d, J=1.6 Hz, 1H), 7.00-7.12 (m, 6H), 7.32 (d,J=1.6 Hz, 1H), 7.34-7.45 (m, 9H) 7.75 (dd, J=8.7, 1.7 Hz, 1H), 7.82-7.97(m, 3H), 8.00 (s, 1H), 8.36 (s, 1H), 8.6 (q, J=4.3 Hz, 1H); HRMS (ESI)m/z Calcd for a C₃₇H₃₄N₃O₃[M+H] 568.2600. Found: 568.2590.

Example 8

To THF (100 mL) and water (63 μg, 3.5 mmol) was added6-[(1S)-1,3-dihydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl-2-nap-hthamide(10.0 g, 17.6 mmol). The reaction mixture was cooled to 10° C., andethyldiisopropylamine (3.41 g, 26.4 mmol) and methanesulfonyl chloride(3.03 g, 26.4 mmol) were successively added thereto, and the mixture wasstirred at room temperature for 1 hr. To the reaction mixture was addeda solution of sodium carbonate (3.73 g, 35.2 mmol) in water (40 mL), andthe mixture was warmed to 57° C., and stirred for 5 hr. The mixture wasconcentrated under reduced pressure to adjust the volume of the residueto 45 mL. Ethyl acetate (50 mL) was added thereto at 45° C., and themixture was stirred. The reaction mixture was stirred with cooling toroom temperature and then cooling to 5° C. The crystals were collectedby filtration, and washed with ethyl acetate (40 mL) cooled to 5° C. Theobtained wet crystals were dried under reduced pressure to give crude6-((7S)-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-na-phthamide(5.3 g, 17.3 mmol). yield 98%.

Example 9

The crude6-((7S)-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamideobtained in Example 8 (5.0 g, 16.3 mmol) was added to methanol (97.5 mL)and purified water (38 mL), and dissolved with heating to 70° C., andactivated carbon (0.25 g) was added thereto. The reaction mixture wasstirred at the same temperature for 20 min, and the activated carbon wasfiltered off, and washed with 72% methanol (5 mL). The filtrate andwashing were combined, and purified water (35.5 mL) was added dropwisethereto at 55 to 60° C. The reaction mixture was stirred with cooling to30° C., purified water (35.5 mL) was added thereto at the sametemperature, and the mixture was stirred. The reaction mixture wasstirred with cooling to 2° C., and the crystals were collected byfiltration, and washed with 45% methanol (15 mL). The obtained wetcrystals were dried under reduced pressure to give6-((7S)-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-na-phthamide(4.17 g, 13.6 mmol). yield 83%. enantiomeric excess: 99% ee.

¹H NMR (500 MHz, DMSO-d₆) δ 2.84 (m, 1H), 2.88 (d, J=4.4 Hz, 3H), 2.93(m, 1H), 4.19 (m, 1H), 4.25 (m, 1H), 6.26 (s, 1H), 6.69 (s, 1H), 7.65(m, 1H), 7.66 (s, 1H), 7.95 (dd, J=8.5, 1.6 Hz, 1H), 8.00 (d, J=8.5 Hz,2H), 8.09 (brs, 1H), 8.45 (brs, 1H), 8.65 (q, J=4.4 Hz, 1H); MS (EI) m/z307 [M]+; Anal. Calcd for a C₁₈H₁₇N₃O₂: C, 70.34; H, 5.58; N, 13.67.Found: C, 70.31; H, 5.50; N, 13.66.

Example 10

To a mixture of toluene (100 mL), THF (20 mL) and 1 mol/L hydrochloricacid (100 mL) was added6-[(1S)-1,3-dihydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide(10.0 g, 17.6 mmol). The reaction mixture was stirred vigorously at 60°C. for 2 hr. The reaction mixture was allowed to cool to roomtemperature. The aqueous layer was separated, and the obtained aqueouslayer was washed twice with methyl tert-butyl ether (100 mL and 50 mL).To the obtained aqueous layer was added methanol (10 mL), and thencarbonate (10.6 g) and water (10 mL) were added thereto. The obtainedslurry was stirred overnight at room temperature. The obtained crystalswere collected by filtration, and washed with 10% aqueous methanol. Theobtained wet crystals were dried under reduced pressure to give crudecrystals (5.56 g). To a mixture of methanol (30 mL) and water (3 mL)were added the crude crystals (4 g). After stirring at 50° C. for 1 hr,water (50 mL) was added to the slurry at 50° C. over 1 hr. The slurrywas stirred at 50° C. for 1 hr, and then allowed to cool to roomtemperature. After stirring for 3 hr at room temperature, the crystalswere collected by filtration and washed with water. The obtained wetcrystals were dried under reduced pressure to give6-[(1S)-1,3-dihydroxy-1-(1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide(3.69 g, 11.3 mmol). yield 89%.

¹H NMR (500 MHz, DMSO-d₆) δ 2.33-2.39 (m, 1H), 2.47-2.52 (m, 1H), 2.83and 2.79 (d, J=4.4 Hz, total 3H), 3.33 (br s, 1H), 3.47 (br s, 1H), 4.54and 4.59 (br s, total 1H), 5.58 and 5.97 (s, total 1H), 6.83 and 6.94(s, total 1H), 7.47 and 7.58 (s, total 1H), 7.53 and 7.75 (d, J=8.5 Hz,total 1H), 7.83-7.99 (m, 3H), 8.03 and 8.06 (s, 1H), 8.36 and 8.38 (s,1H), 8.57 (d, J=4.1 Hz, 1H), 11.75 and 11.83 (s, total 1H); Anal. Calcdfor C₁₈H₁₉N₃O₃: C, 66.45; H, 5.89; N, 12.91; O, 14.75. Found: C, 66.19;H, 5.99; N, 12.72.

Example 11

To a solution of6-[(1S)-1,3-dihydroxy-1-(1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide(1.0 g, 3.1 mmol) in tetrahydrofuran (100 mL) were addedN-ethyldiisopropylamine (2.39 g, 18.4 mmol) and methanesulfonyl chloride(2.11 g, 18.4 mmol) at room temperature. The mixture was stirred at thesame temperature for 3 hr. To the reaction mixture was added a solutionof sodium carbonate (1.31 g, 12.3 mmol) in water (3 mL). The mixture washeated to 60° C. and stirred for 5 hr. After the reaction mixture wasallowed to cool to room temperature, ethyl acetate (25 mL) was addedthereto. The organic layer was separated and concentrated under reducedpressure. Methanol (16.7 mL) and water (6.4 mL) were added to theresidue. The mixture was heated to 65° C., and activated carbon (45 mg)was added thereto. After stirring at the same temperature for 30 min,the activated carbon was filtered off and washed with methanol (1.1 mL).Water (6.4 mL) was added to the filtrate at 55° C. The resulting mixturewas allowed to cool to room temperature and stirred for 30 min. To themixture was added water (6.4 mL) at the same temperature, and themixture was stirred for 2 hr. The mixture was cooled to 0° C. andstirred for 2 hr. The obtained precipitated crystals were collected byfiltration, washed with 45% aqueous methanol (3 mL), and dried underreduced pressure to give6-((7S)-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide(540 mg, 1.8 mmol). yield 57%.

Example 12

Under a nitrogen atmosphere, 6-bromo-N-methyl-2-naphthamide (10.0 g, 38mmol) was added to tetrahydrofuran (250 mL), and then 2.0 mol/Lisopropylmagnesium chloride tetrahydrofuran solution (19 mL) was addeddropwise thereto at room temperature. The obtained reaction mixture wascooled to −20° C., 1.6 mol/L n-butyllithium hexane solution (40 mL) wasadded dropwise to the reaction mixture, and the mixture was stirred atthe same temperature for 2 hr. To the obtained reaction mixture wasadded dropwise a solution of1-N,N-dimethylaminosulfonyl-4-formyl-1H-imidazole (11.6 g, 57 mmol) intetrahydrofuran (200 mL) at −20° C., and the mixture was stirred at thesame temperature for 2 hr. The obtained reaction mixture was allowed towarm to 0° C., and stirred for 1 hr, and 20 w/v % aqueous ammoniumchloride solution (150 mL) was added dropwise to the reaction mixture.The reaction mixture was separated to the organic layer and aqueouslayer, and the obtained organic layer was concentrated to the volume ofabout 90 mL under reduced pressure. To the obtained residue was addedtetrahydrofuran (140 mL), and the obtained reaction mixture wasconcentrated to the volume of about 80 mL under reduced pressure. To theobtained residue was added ethyl acetate (250 mL), and the mixture wasconcentrated to the volume of about 80 mL under reduced pressure. Theseoperations were repeated three times. To the obtained residue was addedethyl acetate to adjust the volume to about 200 mL to give a ethylacetate solution containing6-[hydroxy(1-N,N-dimethylaminosulfonyl-1H-imidazol-4-yl)methyl]-N-methyl-2-naphthamide.

The NMR data of the obtained6-[hydroxy(1-N,N-dimethylaminosulfonyl-1H-imidazol-4-yl)methyl]-N-methyl-2-naphthamidewas shown below.

¹H NMR (500 MHz, DMSO-d₆) δ 2.76-2.88 (m, 9H), 5.82 (s, 1H), 6.08 (s,1H), 7.37-7.43 (m, 1H), 7.61 (dd, J=8.5, 1.58 Hz, 1H), 7.84-8.02 (m,4H), 8.07 (d, J=1.3 Hz, 1H), 8.39 (s, 1H), 8.59 (d, J=4.1 Hz, 1H); HRMS(ESI) m/z Calcd for a C₁₈H₂₁N₄O₄S[m+H]⁺: 389.1205. Found: 389.1273.

Example 13

To the ethyl acetate solution containing6-[hydroxy(1-N,N-dimethylaminosulfonyl-1H-imidazol-4-yl)methyl]-N-methyl-2-naphthamide,which is obtained in Example 10, were added manganese dioxide (20.6 g,237.2 mmol) and ethyl acetate (200 mL), and the mixture was stirred at60° C. for 10 hr. The insoluble material was filtered off from thereaction mixture at the same temperature, and washed with ethyl acetate(200 mL). The filtrate and washing were combined, and concentrated underreduced pressure to adjust the volume to about 300 mL. Water (150 mL)was added thereto, and the organic layer was separated. These operationswere repeated twice. The organic layers were combined, and stirred atroom temperature about for 1 hr. To the reaction mixture was addeddropwise diisopropyl ether (150 mL), and the mixture was stirred at roomtemperature for 2 hr to give crystals. The obtained crystals werecollected by filtration, and washed with a mixed solvent (90 mL) ofdiisopropyl ether/ethyl acetate (2:1, volume ratio) to give wetcrystals. The obtained wet crystals were dried under reduced pressure togiveN-methyl-6-[(1-N,N-dimethylaminosulfonyl-1H-imidazol-4-yl)carbony-1]-2-naphthamide(8.9 g, 22.9 mmol). total yield from 6-bromo-N-methyl-2-naphthamide:60%.

¹H NMR (500 MHz, DMSO-d₆) δ 2.84-2.91 (m, 3H), 2.93 (s, 6H), 8.02 (d,J=8.5 Hz, 1H), 8.14-8.23 (m, 3H), 8.43 (s, 1H), 8.47 (s, 1H), 8.51 (s,1H), 8.71 (d, J=4.4 Hz, 1H), 8.94 (s, 1H); HRMS (ESI) m/z Calcd for aC₁₈H₁₉N₄O₄S[m+H]⁺: 387.1049. Found: 387.1118.

Example 14

Under a nitrogen atmosphere, zinc powder (15.0 g, 229.4 mmol) wassuspended in tetrahydrofuran (57 mL), trimethylsilyl chloride (1.5 mL,11.5 mmol) was added thereto at room temperature, and the mixture wasstirred for 30 min. The reaction mixture was heated to 40° C., and tothe reaction mixture was added dropwise a solution of ethyl bromoacetate(12.7 mL, 114.5 mmol) in tetrahydrofuran (144 mL). The obtained reactionmixture was stirred at 30 min for 40° C., and kept stand at roomtemperature, and the excess amount of zinc was filtered off to give areaction mixture containing bromo(2-ethoxy-2-oxoethyl)zinc (hereinafterto be abbreviated as Reformatsky reagent). The obtained Reformatskyreagent (49.7 mL, corresponding to 2.5 eq.) was cooled to 0° C. orbelow, and to the Reformatsky reagent were added cinchonine (3.8 g, 12.9mmol), pyridine (3.4 mL, 41.4 mmol) and tetrahydrofuran (32 mL). Theobtained reaction mixture was stirred for 15 min, and cooled to −20° C.,and to the reaction mixture were addedN-methyl-6-[(1-N,N-dimethylaminosulfonyl-1H-imidazol-4-yl)carbonyl]-2-naphthamide(4.0 g, 10.4 mmol) and tetrahydrofuran (12 mL). The obtained reactionmixture was stirred at −20° C. for 1 hr. To the obtained reactionmixture was added the Reformatsky reagent (25.0 mL, corresponding to1.25 eq.) at −20° C., the obtained reaction mixture was stirred for 30min. To the obtained reaction mixture were added ethyl acetate (100 mL)and 20 w/v % aqueous citric acid solution (100 mL) at 10° C. or below.The separated organic layer was washed with 10% sodiumchloride-containing 20 w/v % aqueous citric acid solution (100 mL) at 5°C. (twice), 5 w/v % aqueous sodium bicarbonate (100 mL) (three times),and the water (100 mL). The organic layer was concentrated to the volumeof 20 mL under reduced pressure to give a residue. To the obtainedresidue was added methanol (50 mL), and the mixture was concentrated tothe volume of 20 mL under reduced pressure to give a residue. Theseoperations were repeated again. To the obtained residue was added water(8 mL), and the obtained solution was stirred for 1 hr. To the reactionmixture was added dropwise water (32 mL), and the mixture was stirred togive crystals. The obtained crystals were collected by filtration, andwashed with a mixed solvent (30 mL) of methanol/water (1:3, volumeratio) to give wet crystals. The obtained wet crystals were dried underreduced pressure to giveethyl(3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-N,N-dimethyl-aminosulfonyl-1H-imidazol-4-yl)propanoate(4.29 g, 9.04 mmol). yield 87%. enantiomeric excess: 85% ee.

¹H NMR (500 MHz, DMSO-d₆) δ 0.94 (t, J=7.1 Hz, 3H), 2.78 (s, 6H), 2.84(d, J=4.7 Hz, 3H), 3.21-3.31 (m, 1H), 3.31-3.42 (m, 1H), 3.80-3.95 (m,2H), 6.12 (s, 1H), 7.38 (d, J=1.6 Hz, 1H), 7.75 (dd, J=8.7, 1.73 Hz,1H), 7.85-7.99 (m, 3H), 8.06-8.14 (m, 2H), 8.38 (s, 1H), 8.58 (d, J=4.4Hz, 1H); HRMS (ESI) m/z Calcd for a C₂₂H₂₇N₄O₆S[m+H]⁺: 475.1573. Found:475.1635.

Example 15

To a solution of anhydrous calcium chloride (2.05 g, 18.5 mmol) inethanol (26.5 mL) was added sodium borohydride (1.40 g, 36.9 mmol) at−17° C., and the mixture was stirred at −16-−7° C. for 30 min. To theobtained reaction mixture was added dropwise a solution ofethyl(3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-N,N-dimethyl-aminosulfonyl-1H-imidazol-4-yl)propanoate(3.5 g, 7.38 mmol) in tetrahydrofuran (36 mL) at −20° C. The obtainedreaction mixture was stirred for 6 hr at 0° C., to the reaction mixturewere added dropwise water (36 mL), 1 mol/L hydrochloric acid (37 mL) andethyl acetate (90 mL) at 5° C., and the mixture was stirred. To theseparated organic layer was added 0.2 mol/L hydrochloric acid (37 mL) at5° C., and the mixture was stirred, and adjusted about pH 7.5 with 0.5mol/L aqueous sodium hydroxide solution at 5° C. To the separatedorganic layer was added again 0.2 mol/L hydrochloric acid (37 mL) at 5°C., and the mixture was stirred, and adjusted to about pH 7.5 with 0.5mol/L aqueous sodium hydroxide solution at the same temperature. To theseparated organic layer was added water (45 mL), and the mixture wasadjusted to about pH 9.5 with 0.5 mol/L aqueous sodium hydroxidesolution. The separated organic layer was washed with 10 w/v % brine (45mL). To the separated organic layer was added water (54 mL), and themixture was heated to 60° C., and stirred for 4 hr. The separatedorganic layer was completely concentrated under reduced pressure to give6-[1S)-1,3-dihydroxy-1-(1-N,N-dimethylaminosulfonyl-1H-imidazol-4-yl)pro-pyl]-N-methyl-2-naphthamide(2.1 g, 4.83 mmol). yield 66%. enantiomeric excess: 86% ee.

¹H NMR (500 MHz, DMSO-d₆) δ 2.34-2.47 (m, 1H), 2.78 (s, 6H), 2.82-2.86(m, 3H), 3.35-3.48 (m, 2H), 4.50 (t, J=4.9 Hz, 1H), 5.92 (s, 1H), 7.36(d, J=1.3 Hz, 1H), 7.76 (dd, J=8.7, 1.73 Hz, 1H), 7.87-7.98 (m, 3H),8.06-8.14 (m, 2H), 8.37 (s, 1 H), 8.57 (q, J=4.3 Hz, 1H); HRMS (ESI) m/zCalcd for a C₂₀H₂₅N₄O₅S[m+H]⁺: 433.1467. Found: 433.1535.

Example 16

Under a nitrogen atmosphere, 6-bromo-N-methyl-2-naphthamide (10.0 g,37.9 mmol) was added to tetrahydrofuran (250 mL), and to the obtainedsolution was added dropwise 2.0 mol/L isopropylmagnesium chloridetetrahydrofuran solution (18.9 mL) at room temperature. The obtainedreaction mixture was cooled to −30° C., 1.65 mol/L n-butyllithium hexanesolution (37.9 mL) was added dropwise thereto, and the mixture wasstirred at the same temperature for 1 hr or more. To the obtainedreaction mixture was added dropwise a solution of1-tosyl-4-formyl-1H-imidazole (14.2 g, 56.8 mmol) in tetrahydrofuran(200 mL) at −20° C., and the mixture was stirred at the same temperaturefor 2 hr. The obtained reaction mixture was warmed over 2 hr to 0° C.,20 w/v % aqueous ammonium chloride solution (150 mL) was added dropwisethereto. The separated organic layer was concentrated to the volume ofabout 130 mL under reduced pressure to give a residue. To the obtainedresidue was added tetrahydrofuran (200 mL), and the mixture wasconcentrated to the volume of about 130 mL under reduced pressure togive a residue. To the obtained residue was added acetone (200 mL), andthe mixture was concentrated to the volume of about 200 mL under reducedpressure. These operations were repeated three times to give a residue.To the obtained residue was added acetone to adjust the volume to about260 mL. The obtained solution was stirred at room temperature for 2 hror more. The obtained crystals were collected by filtration, and washedwith acetone (100 mL) to give wet crystals. The obtained wet crystalswere dried under reduced pressure at an outside temperature of 50° C. togive 6-(hydroxy(1-tosyl-1H-imidazol-4-yl)methyl)-N-methyl-2-naphthamide(8.5 g, 19.5 mmol). yield 52%.

¹H NMR (500 MHz, DMSO-d₆) δ 2.40 (s, 3H), 2.83 (d, J=5.0 Hz, 1H), 5.74(d, J=5.0 Hz, 1H), 6.05 (d, J=5.0 Hz, 1H), 7.49-7.51 (m, 3H), 7.55-7.56(m, 1H), 7.88-7.92 (m, 4H), 7.98-7.99 (m, 2H), 8.27 (s, 1H), 8.37 (s,1H), 8.58-8.59 (q, J=5.0 Hz, 1H); HRMS (ESI) m/z Calcd for aC₂₃H₂₂N₃O₄S[m+H] 436.1286. Found: 436.1322.

Example 17

6-(Hydroxy(1-tosyl-1H-imidazol-4-yl)methyl)-N-methyl-2-naphthamide (8.2g, 18.8 mmol) and manganese dioxide (14.7 g, 169.1 mmol) were added toN,N-dimethylacetamide (70 mL), and the mixture was stirred at 60° C. for7 hr. The insoluble material was filtered off from the obtained reactionmixture at 60° C., and washed with N,N-dimethylacetamide (33 mL). Thefiltrate and washing were combined, and cooled to 40° C., water (49 mL)was added dropwise thereto, and the mixture was stirred at the sametemperature for 0.5 hr or more, and then at room temperature for 1 hr ormore to give crystals. The obtained crystals were collected byfiltration, and washed with water (51 mL) to give wet crystals. Theobtained wet crystals were dried under reduced pressure at an outsidetemperature of 50° C. to give crude crystals (6.6 g). Ethyl acetate (66mL) were warmed to 40° C., and the crude crystals (6.6 g) were addedthereto. The obtained mixture was warmed to 50° C., and stirred for 0.5hr or more, and 13 mL of the solvent was evaporated under reducedpressure. The obtained residue was allowed to cool to room temperature,diisopropyl ether (53 mL) was added dropwise thereto at the sametemperature, and the mixture was stirred to give crystals. The obtainedcrystals were collected by filtration, and washed with a mixed solvent(20 mL) of diisopropyl ether/ethyl acetate (1:1, volume ratio) to givewet crystals. The obtained wet crystals were dried under reducedpressure at an outside temperature of 50° C. to giveN-methyl-6-[(1-tosyl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (6.5 g,15.0 mmol). yield 79%.

¹H NMR (500 MHz, DMSO-d₆) δ 2.42 (s, 3H), 2.85 (d, J=5.0 Hz, 3H),7.55-7.56 (m, 2H), 8.01-8.02 (m, 1H), 8.12-8.17 (m, 5H), 8.49 (s, 1H),8.61-8.64 (d, J=15.0 Hz, 2H), 8.69 (q, 1H), 8.86 (s, 1H); HRMS (ESI) m/zCalcd for a C₂₃H₂₀N₃O₄S[m+H]⁺: 434.1130. Found: 434.1168.

Example 18

The Reformatsky reagent was obtained according to the method describedin Example 14. The obtained Reformatsky reagent (27.1 mL, correspondingto 2.5 eq.) was cooled to 0° C., cinchonine (2.1 g, 7.2 mmol) andpyridine (1.9 mL, 23.0 mmol) was added thereto, and the mixture wasstirred at the same temperature for 30 min. The reaction mixture wascooled to −25° C.,N-methyl-6-[(1-tosyl-1H-imidazol-4-yl)carbonyl]-2-naphthamide (2.5 g,5.76 mmol) was added thereto, and the mixture was stirred at the sametemperature for 1 hr. To the obtained reaction mixture was added theReformatsky reagent (10.9 mL, corresponding to 1.0 eq.) at −25° C., andthe mixture was stirred for 1 hr. The Reformatsky reagent (5.4 mL,corresponding to 0.5 eq.) was added again −25° C., and the mixture wasstirred for 1 hr. To the obtained reaction mixture were added ethylacetate (35 mL) and 20 w/v % aqueous citric acid solution (35 mL) at 10°C. or below. The separated organic layer was washed with 10% sodiumchloride-containing 20 w/v % aqueous citric acid solution (35 mL) at5.degree. C. (twice), 5 w/v % aqueous sodium bicarbonate (35 mL) (threetimes), and water (35 mL). The separated organic layer was concentratedunder reduced pressure to giveethyl(3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-tosyl-1H-imi-dazol-4-yl)propanoate(2.92 g, 5.6 mmol). yield: 97%.

¹H NMR (500 MHz, DMSO-d₆) δ 0.79 (t, J=7.1 Hz, 3H), 2.39 (s, 3H), 2.83(d, J=4.7 Hz, 3H), 3.19 (d, J=14.2 Hz, 1H), 3.30 (d, J=14.2 Hz, 1H),3.76 (t, J=6.9 Hz, 2H), 6.13 (s, 1H), 7.44-7.52 (m, 3H), 7.68 (dd,J=8.7, 2.1 Hz, 1H), 7.85-7.94 (m, 3H), 7.97 (d, J=8.2 Hz, 2H), 8.00-8.03(m, 1H), 8.26-8.41 (m, 2H), 8.57 (d, J=4.7 Hz, 1H).

Example 19

To a solution of anhydrous calcium chloride (1.86 g, 16.3 mmol) inethanol (32 mL) were added sodium borohydride (1.27 g, 33.6 mmol) andethanol (5 mL) at −10° C., and the mixture was stirred at −10° C. for 30min. To the reaction mixture were added dropwise a solution of ethyl(3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-tosyl-1H-imi-dazol-4-yl)propanoate (2.5 g, 5.6 mmol) intetrahydrofuran (73 mL)/ethanol (10 mL), and tetrahydrofuran (5 mL) at−10° C. The obtained reaction mixture was stirred at 5° C. for 6 hr, andto the obtained reaction mixture were added dropwise water (100 mL), 1mol/L hydrochloric acid (40 mL) and ethyl acetate (200 mL) at 10° C. orbelow, and the mixture was stirred. To the separated organic layer wasadded 0.2 mol/L hydrochloric acid (14 mL) at 5° C., and the mixture wasstirred. The reaction mixture was adjusted to pH 7.5 with 0.5 mol/Laqueous sodium hydroxide solution at 5° C. To the separated organiclayer was added again 0.2 mol/L hydrochloric acid (14 mL) at 5° C., andthe mixture was stirred. The reaction mixture was adjusted to pH 7.5with 0.5 mol/L aqueous sodium hydroxide solution at 5° C. To theseparated organic layer was added water (10 mL), and the mixture wasadjusted to pH 9.5 with 0.5 mol/L aqueous sodium hydroxide solution. Tothe separated organic layer was added water (120 mL), and the mixturewas heated to 60° C., and stirred for 3 hr. The separated organic layerwas concentrated at 60° C. under reduced pressure to give6-[(1S)-1,3-dihydroxy-1-(1-tosyl-1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide(2.9 g, 6.1 mmol).

¹H NMR (500 MHz, DMSO-d₆) δ 2.36-2.47 (m, 1H), 2.38 (d, J=2.5 Hz, 3H),2.59-2.71 (m, 1H), 2.83 (d, J=4.7 Hz, 3H), 3.61-3.68 (m, 1H), 3.68-3.76(m, 1H), 4.45-4.47 (m, 1H), 5.91 (s, 1H), 7.42-7.45 (m, 1H), 7.45-7.51(m, 2H), 7.68 (dt, J=8.7, 2.1 Hz, 1H), 7.72 (s, 1H), 7.84-7.93 (m, 2H),7.93-8.03 (m, 4H), 8.27-8.40 (m, 2H), 8.48-8.65 (m, 1H).

Example 20

To a solution of anhydrous calcium chloride (1.86 g, 16.3 mmol) inethanol (32 mL) were added sodium borohydride (1.27 g, 33.6 mmol) andethanol (5 mL) at −10° C., and the mixture was stirred at −10° C. for 30min. To the reaction mixture was added dropwise a solution ofethyl(3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-tosyl-1H-imi-dazol-4-yl)propanoate(2.5 g, 5.6 mmol) in tetrahydrofuran (73 mL)/ethanol (10 mL), andtetrahydrofuran (5 mL) at −10° C. The obtained reaction mixture wasstirred at 7° C. for 21 hr, and to the obtained reaction mixture wereadded dropwise water (100 mL), 1 mol/L hydrochloric acid (40 mL) andethyl acetate (200 mL) at 10° C. or below, and the mixture was stirred.To the separated organic layer was added 0.2 mol/L hydrochloric acid (14mL) at 5° C., and the mixture was stirred. The reaction mixture wasadjusted to pH 7.5 with 0.5 mol/L aqueous sodium hydroxide solution at5° C. To the separated organic layer was added again 0.2 mol/Lhydrochloric acid (14 mL) at 5° C., and the mixture was stirred. Thereaction mixture was adjusted to pH 7.5 with 0.5 mol/L aqueous sodiumhydroxide solution at 5° C. To the separated organic layer was addedwater (10 mL), and the mixture was adjusted to pH 9.5 with 0.5 mol/Laqueous sodium hydroxide solution. To the separated organic layer wasadded water (120 mL), and the mixture was heated to 60° C., and stirredfor 3 hr. The separated organic layer was concentrated at 60° C. underreduced pressure to give6-[(1S)-1,3-dihydroxy-1-(1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide(2.3 g, 7.0 mmol).

Example 21

To THF (4.8 mL) was added6-[(1S)-1,3-dihydroxy-1-(1-tosyl-1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide(479.6 mg, 1.0 mmol). The reaction mixture was cooled to 10° C., andethyldiisopropylamine (505.9 mg, 4.0 mmol) and methanesulfonyl chloride(458.8 mg, 4.0 mmol) were successively added thereto, and the mixturewas stirred at room temperature for 2 hr. To the reaction mixture wasadded a solution of sodium carbonate (530.0 mg, 5.0 mmol) in water (2mL), and the mixture was warmed to 57° C., and stirred for 5 hr. Theseparated organic layer was concentrated under reduced pressure.Methanol (4 mL) and activated carbon (40 mg) were added thereto. Thereaction mixture was stirred at the same temperature for 20 min, and theactivated carbon was filtered off, and washed with methanol (2 mL). Thefiltrate and washing were concentrated under reduced pressure. Methanol(1 mL), ethyl acetate (5 mL), and THF (10 mL) were added to the residue,and the mixture was washed twice with 10% sodium chloride-containing 5w/v % aqueous sodium bicarbonate solution (15 mL). The separated organiclayer was concentrated under reduced pressure to give6-(7S)-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide(135.4 mg, 0.44 mmol). yield 44%.

Example 22

Under a nitrogen atmosphere, 6-bromo-N-methyl-2-naphthamide (10.0 g,37.9 mmol) was added to tetrahydrofuran (250 mL), and to the obtainedsolution was added dropwise 2.0 mol/L isopropylmagnesium chloridetetrahydrofuran solution (18.9 mL) at room temperature. The obtainedreaction mixture was cooled to −30° C., 1.65 mol/L n-butyllithium hexanesolution (37.9 mL) was added dropwise thereto, and the mixture wasstirred at the same temperature for 1 hr or more. To the reactionmixture was added dropwise a solution of1-(phenylsulfonyl)-4-formyl-1H-imidazole (13.4 g, 56.8 mmol) intetrahydrofuran (100 mL) at −20° C., and the mixture was stirred at thesame temperature for 2 hr. The reaction mixture was warmed over 2 hr to0° C., and 20 w/v % aqueous ammonium chloride solution (150 mL) wasadded dropwise thereto. The separated organic layer was concentrated tothe volume of about 130 mL under reduced pressure to give a residue. Tothe obtained residue was added tetrahydrofuran (200 mL), and the mixturewas concentrated to the volume of about 130 mL under reduced pressure togive a residue. To the obtained residue was added ethyl acetate (200mL), and the mixture was concentrated to the volume of about 200 mLunder reduced pressure. These operations were repeated three times togive a residue. To the obtained residue was added ethyl acetate toadjust the volume to about 200 mL. The obtained reaction mixture wasstirred at room temperature for 2 hr or more to give crystals. Thecrystals was collected by filtration, and washed with ethyl acetate (100mL) to give wet crystals. The obtained wet crystals were dried underreduced pressure at an outside temperature of 50° C. to give6-(hydroxy(1-(phenylsulfonyl)-1H-imidazol-4-yl)methyl)-N-methyl-2-naphthamide(9.2 g, 21.8 mmol). yield 58%.

¹H NMR (500 MHz, DMSO-d₆) δ 2.83 (d, J=5.0 Hz, 3H), 5.74 (d, J=5.0 Hz,1H), 6.06 (d, J=5.0 Hz, 1H), 7.69-7.72 (m, 2H), 7.81-7.84 (m, 1H),7.90-7.94 (m, 4H), 8.11-8.13 (m, 2H), 8.30 (s, 1H), 8.37 (s, 1H),8.57-8.59 (q, 1H).

Example 23

6-(Hydroxy(1-(phenylsulfonyl)-1H-imidazol-4-yl)methyl)-N-methyl-2-naphthamide(8.8 g, 20.88 mmol) and manganese dioxide (16.4 g, 187.9 mmol) wereadded to N,N-dimethylacetamide (75 mL), and the mixture was stirred at60° C. for 9.5 hr. The insoluble material was filtered off from thereaction mixture at 60° C., and washed with DMAc (35 mL). The filtrateand washing were combined, and cooled to 40° C., water (53 mL) was addeddropwise thereto, and the mixture was stirred at the same temperaturefor 0.5 hr or more, and then at room temperature for 1 hr or more togive crystals. The obtained crystals were collected by filtration, andwashed with water (44 mL) to give wet crystals. The obtained wetcrystals were dried under reduced pressure at an outside temperature of50° C. to give crude crystals (6.3 g). Ethyl acetate (63 mL) was warmedto 40° C., and the crude crystals (6.3 g) were added thereto. Theobtained mixture was warmed to 50° C., and stirred for 0.5 hr or more.13 mL of the solvent was evaporated under reduced pressure to give aresidue. The obtained residue was allowed to cool to room temperature,diisopropyl ether (53 mL) was added dropwise thereto at the sametemperature, and the mixture was stirred to give crystals. The obtainedcrystals were collected by filtration, and washed with a mixed solvent(20 mL) of diisopropyl ether/ethyl acetate (1:1, volume ratio) to givewet crystals. The obtained wet crystals were dried under reducedpressure at an outside temperature of 50° C. to giveN-methyl-6-[(1-(phenylsulfonyl)-1H-imidazol-4-yl)carbonyl]-2-naphthamide(6.2 g, 14.9 mmol). yield 72%.

¹H NMR (500 MHz, DMSO-d₆) δ 2.86 (d, J=5.0 Hz, 3H), 7.76 (t, J=10.0 Hz,2H), 7.88 (t, J=10.0 Hz, 1H), 8.00 (d, J=10.0 Hz, 1H), 8.12 (q, J=5.0Hz, 2H), 8.18 (d, J=10.0 Hz, 1H), 8.27 (d, J=10.0 Hz, 2H), 8.49 (s, 1H),8.67 (d, J=10.0 Hz, 2H), 8.71 (q, J=5.0 Hz, 1H), 8.86 (s, 1H).

Example 24

The Reformatsky reagent was obtained according to the method describedin Example 14. The obtained Reformatsky reagent (27.3 mL, correspondingto 2.5 eq.) was cooled to 0° C. or below, cinchonine (2.6 g, 8.9 mmol),pyridine (2.3 mL, 23.0 mmol) and THF (24 mL) were added thereto, and themixture was stirred at the same temperature for 30 min. The reactionmixture was cooled to −25° C.,N-methyl-6-((1-phenylsulfonyl-1H-imidazol-4-yl)carbonyl)-2-naphthamide(3.0 g, 7.2 mmol) was added thereto. The obtained reaction mixture wasstirred at −20° C. for 1 hr. To the obtained reaction mixture was addedthe Reformatsky reagent (10.9 mL, corresponding to 1.0 eq.) at −25° C.,and the mixture was stirred for 1.5 hr. The Reformatsky reagent (10.9mL, corresponding to 1.0 eq.) was added again thereto −25° C., and themixture was stirred for 1.5 hr. To the obtained reaction mixture wereadded ethyl acetate (42 mL) and 20 w/v % aqueous citric acid solution(42 mL) at 10° C. or below. The separated organic layer was washedsuccessively with 10% sodium chloride-containing 20 w/v % aqueous citricacid solution (30 mL, twice) at 5° C., 5 w/v % aqueous sodiumbicarbonate (30 mL, three times), and water (30 mL). The organic layerwas concentrated to the volume of 18 mL under reduced pressure to give aresidue. To the obtained residue was added methanol (30 mL), and themixture was concentrated to the volume of 18 mL under reduced pressureto give a residue. To the residue was added methanol to adjust thevolume to 30 mL. Water (3 mL) was added thereto at room temperature, andthe mixture was stirred for 1 hr. Then water (21 mL) was added dropwisethereto at the same temperature, and the mixture was stirred. Theobtained crystals were collected by filtration, and washed with a mixedsolvent (9 mL) of methanol/water (1:3, volume ratio). The obtained wetcrystals were dried under reduced pressure to giveethyl(3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-phenylsulfon-yl-1H-imidazol-4-yl)propanoate(3.2 g, 6.3 mmol). yield 88%. enantiomeric excess: 61% ee.

¹H NMR (500 MHz, DMSO-d₆) δ 0.78 (t, J=5.0 Hz, 3H), 2.82 (d, J=5.0 Hz,3H), 3.19 (d, J=15.0 Hz, 1H), 3.30 (d, J=15.0 Hz, 1H), 3.76 (q, J=5.0Hz, 2H), 6.15 (s, 1H), 7.50 (d, J=5.0 Hz, 1H), 7.69 (dd, J=15.0, 10.0Hz, 3H), 7.79 (t, J=/010.0 Hz, 1H), 7.87-7.92 (m, 3H), 8.02 (s, 1H),8.09-8.12 (m, 2H), 8.34 (s, 1H), 8.58 (q, J=5.0 Hz, 1H).

Example 25

To a solution of anhydrous calcium chloride (0.84 g, 7.4 mmol) inethanol (9 mL) was added sodium borohydride (0.57 g, 14.8 mmol) at −15°C., and the mixture was stirred at −10° C. for 30 min. To the reactionmixture was added dropwise a solution ofethyl(3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-phenylsulfon-yl-1H-imidazol-4-yl)propanoate(1.5 g, 3.0 mmol) in tetrahydrofuran (75 mL)/ethanol (15 mL) at −10° C.The obtained reaction mixture was stirred at 5° C. for 8 hr, and to theobtained reaction mixture were added dropwise water (12 mL), 1 mol/Lhydrochloric acid (15 mL) and ethyl acetate (30 mL) at 10° C. or below,and the mixture was stirred. To the separated organic layer was added0.2 mol/L hydrochloric acid (15 mL) at 5° C., and the mixture wasstirred. The reaction mixture was adjusted to pH 7.5 with 0.5 mol/Laqueous sodium hydroxide solution at 5° C. To the separated organiclayer was added again 0.2 mol/L hydrochloric acid (15 mL) at 5° C., andthe mixture was stirred. The reaction mixture was adjusted to pH 7.5with 0.5 mol/L aqueous sodium hydroxide solution at 5° C. To theseparated organic layer was added water (15 mL), and the mixture wasadjusted to pH 9.5 with 0.5 mol/L aqueous sodium hydroxide solution. Theseparated organic layer was washed with 10 w/v % brine (15 mL). To theseparated organic layer was added water (18 mL), and the mixture washeated to 60° C., and stirred for 3 hr. The separated organic layer wasconcentrated under reduced pressure to give6-[(1S)-1,3-dihydroxy-1-(1-phenylsulfonyl-1H-imidazol-4-yl)propyl]-N-meth-yl-2-naphthamide(1.2 g, 2.5 mmol). yield 83%. enantiomeric excess: 62% ee.

¹H NMR (500 MHz, DMSO-d₆) δ 2.13-2.17 (m, 1H), 2.34-2.42 (m, 1H), 2.83(d, J=5.0 Hz, 3H), 3.52-3.54 (m, 2H), 4.49 (t, J=5.0 Hz, 1H), 5.38 (s,1H), 7.28-7.33 (m, 2H), 7.48 (d, J=5.0 Hz, 1H), 7.70 (dd, J=10.0, 5.0Hz, 3H), 7.80 (t, J=10.0 Hz, 1H), 7.95-8.01 (m, 3H), 8.04-8.12 (m, 1H),8.34 (s, 1H), 8.45 (s, 1H), 8.62 (q, J=5.0 Hz, 1H); HRMS (ESI) m/z calcdfor C₂₄H₂₄N₃O₅S [m+H]⁺: 466.1392. Found: 466.1436.

Example 26

Under a nitrogen atmosphere, 6-bromo-N-methyl-2-naphthamide (5.0 g, 18.9mmol) was added to tetrahydrofuran (125 mL), and to the obtainedsolution was added dropwise 2.0 mol/L isopropylmagnesium chloridetetrahydrofuran solution (9.5 mL) at room temperature. The obtainedreaction mixture was cooled to −30° C., 1.65 mol/L n-butyllithium hexanesolution (18.9 mL) was added dropwise thereto, and the mixture wasstirred at the same temperature for 1 hr or more. To the reactionmixture was added dropwise a solution of t-butyl4-formyl-1H-imidazole-1-carboxylate (6.7 g, 34.1 mmol) intetrahydrofuran (50 mL) at −20° C., and the mixture was stirred at thesame temperature for 2 hr. The obtained reaction mixture was warmed over2 hr to 0° C., and 20 w/v % aqueous ammonium chloride solution (75 mL)was added dropwise thereto. The separated organic layer was concentratedto the volume of about 65 mL under reduced pressure to give a residue.To the obtained residue was added tetrahydrofuran (100 mL), and themixture was concentrated to the volume of about 65 mL under reducedpressure to give a residue. To the obtained residue was added acetone(100 mL), and the mixture was concentrated to the volume of about 100 mLunder reduced pressure. These operations were repeated three times togive a residue. The obtained residue was concentrated to dryness to givet-butyl4-(hydroxy(6-methylcarbamoyl)naphthalen-2-yl)methyl)-1H-imidazole-1-carboxylate(10.5 g). HRMS (ESI) m/z Calcd for a C₂₁H₂₄N₃O₄ [m+H]⁺; 382.1722. Found:382.1759.

Example 27

t-Butyl4-(hydroxy(6-methylcarbamoyl)naphthalen-2-yl)methyl)-1H-imidazole-1-carboxylate(10.2 g) and manganese dioxide (15.0 g, 172.5 mmol) were added toN,N-dimethylacetamide (35 mL), and the mixture was stirred at 60° C. for14 hr. The insoluble material was filtered off from the obtainedreaction mixture at 60° C., and washed with N,N-dimethylacetamide (25mL). The filtrate and washing were combined, and concentrated underreduced pressure, and to the obtained residue were added ethyl acetate(100 mL) and water (50 mL). The separated organic layer was concentratedunder reduced pressure to give t-butyl4-(6-(methylcarbamoyl)-2-naphthoyl)-1H-imidazole-1-carboxylate (11.4 g).

HRMS (ESI) m/z calcd for a C₂₁H₂₄N₃O₄ [M+H]⁺; 380.1566. Found: 380.1607.

INDUSTRIAL APPLICABILITY

According to the production method of the present invention, imidazolederivatives useful for the prophylaxis or treatment of diseases, forwhich androgen or estrogen is an aggravating factor, can be producedefficiently and industrially under mild conditions.

This application is based on patent application No. 2011-133712 filed inJapan, the contents of which are encompassed in full herein.

1. (canceled)
 2. A method of producing 6-(7-hydroxy-6,7-dihydro-5H-5 pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide or a salt thereof, which comprises Step (1): a step of reacting a compound represented by the formula:

wherein R¹ is an iodine atom or a bromine atom, with a compound represented by the formula: R²—MgX   (II) wherein R² is a C₁₋₆ alkyl group or a C₆₋₁₂ aryl group; and X is a chlorine atom, a bromine atom or an iodine atom, or a compound represented by the formula: R²R^(2′)—Mg   (III) wherein R^(2′) is a C₁₋₆ alkyl group or a C₆₋₁₂ aryl group; and R² is as defined above, and a compound represented by the formula: R³—Li   (IV) wherein R³ is a C₁₋₆ alkyl group or a C₆₋₁₂ aryl group, and then reacting the resulting compound with a compound represented by the formula:

wherein PG is a protecting group, or a salt thereof; Step (2): a step of subjecting a compound represented by the formula:

wherein PG is as defined above, or a salt thereof, which is obtained in Step (1), to oxidation; Step (3): a step of reacting a compound represented by the formula:

wherein PG is as defined above, or a salt thereof, which is obtained in Step (2), with a compound represented by the formula: BrZnCH₂CO₂—R⁴   (VIII) wherein R⁴ is a C₁₋₆ alkyl group; Step (4): a step of subjecting a compound represented by the formula:

wherein each symbol is as defined above, or a salt thereof, which is obtained in Step (3), to reduction; and Step (5): a step of subjecting a compound represented by the formula:

wherein PG is as defined above, or a salt thereof, which is obtained in Step (4), to cyclization and deprotection.
 3. A method of producing of a compound represented by the formula:

wherein PG is a protecting group; and R⁴ is a C₁₋₆ alkyl group, or a salt thereof, which comprises Step (3a): a step of reacting a compound represented by the formula:

wherein PG is as defined above, or a salt thereof, with a compound represented by the formula: BrZnCH₂CO₂—R⁴   (VIII) wherein R⁴ is as defined above, and then adding citric acid to the obtained reaction mixture.
 4. A method of producing of 6-(7-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-napht-hamide or a salt thereof, which comprises Step (3a): a step of reacting a compound represented by the formula:

wherein PG is a protecting group, or a salt thereof, with a compound represented by the formula: BrZnCH₂CO₂—R⁴   (VIII) wherein R⁴ is a C₁₋₆ alkyl group, and then adding citric acid to the obtained reaction mixture; Step (4): a step of subjecting a compound represented by the formula:

wherein each symbol is as defined above, or a salt thereof, which is obtained in Step (3a), to reduction; and Step (5): a step of subjecting a compound represented by the formula:

wherein PG is as defined above, or a salt thereof, which is obtained in Step (4), to cyclization and deprotection.
 5. The method of claim 2, wherein PG is trityl.
 6. The method of claim 2, wherein PG is tosyl, benzenesulfonyl or N,N-dimethylaminosulfonyl.
 7. The method of claim 2, wherein Step (3) is Step (3a): a step of reacting a compound represented by the formula:

wherein PG is a protecting group, or a salt thereof, with a compound represented by the formula: BrZnCH₂CO₂—R⁴   (VIII) wherein R⁴ is a C₁₋₆ alkyl group, and then adding citric acid to the obtained reaction mixture. 